Multitarget Antitumor Effects of Natural Products and Approved Drug Repurposing in Lung Cancer: Advances in Mechanisms, Combination Regimens, Delivery System Optimization, and Clinical Challenges

1. Introduction

Lung cancer remains one of the malignant tumors with the highest incidence and mortality rates worldwide, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of all cases, thereby continuing to pose a significant public health burden. In recent years, the rapid development of targeted therapy and immunotherapy has markedly improved survival outcomes for some NSCLC patients, marking a transition in the treatment of advanced lung cancer from traditional chemotherapy to precision therapy [1,2,3]. However, the clinical benefits of current therapeutic strategies remain limited, as issues such as diminished efficacy, acquired resistance, recurrence, metastasis following disease progression, and associated toxicities continue to represent core challenges that hinder long-term disease control [3,4,5]. Further studies have revealed that NSCLC exhibits considerable heterogeneity concerning driver genes, tumor immune microenvironment, and metabolic status [6,7]. There are substantial differences in sensitivity and tolerance to identical treatment regimens among different patients, which serves as an important biological basis for the instability of therapeutic efficacy and the evolution of drug resistance [8,9,10].

Investigating the fundamental molecular processes and the micro environmental features of non-small cell lung cancer (NSCLC) while developing more targeted treatment approaches based on these insights not only clarifies the critical mechanisms underlying tumor growth and resistance to therapy but also offers a substantial theoretical foundation and justification for refining patient classification, boosting long-term disease management outcomes, and increasing clinical advantages [11,12,13].

In this context, the utilization of natural products and the repurposing of approved drugs have emerged as significant complementary strategies in the development of lung cancer therapeutics [14,15,16]. Natural products are distinguished by their diverse sources, rich structural frameworks, and multi-target regulatory capabilities [17,18,19]. Existing studies have demonstrated that certain natural products can inhibit tumor growth by inducing ferroptosis in NSCLC and lung adenocarcinoma, while also affecting the proliferation, migration, and invasion of tumor cells [20]. In contrast to the de novo development of novel molecules, the repurposing of approved drugs capitalizes on established safety profiles, pharmacokinetic data, and prior clinical experiences to identify new indications for lung cancer within a reduced timeframe [21,22]. This approach not only mitigates development risks but also enhances translational efficiency [20,23].

In recent years, the research focus on tumor cell death modalities has expanded from traditional apoptosis to include regulated cell death patterns such as ferroptosis, autophagy-dependent death, and necroptosis [24,25,26]. The interplay among these mechanisms has opened new avenues for understanding drug resistance in lung cancer and identifying strategies for sensitization [27,28]. In the context of lung cancer, ferroptosis is closely associated with treatment resistance, immune response, and metabolic vulnerability [29,30]. The interactions between autophagy and ferroptosis, as well as the disruption of mitochondrial homeostasis, have been repeatedly shown to influence the sensitivity of tumor cells to therapeutic agents [15,31,32]. Numerous studies indicate that natural products and conventional drugs not only exert their effects by directly killing tumor cells but can also induce ferroptosis by perturbing lipid peroxidation, glutathione metabolism, iron homeostasis, and mitochondrial function [33,34]. Additionally, these compounds can activate signaling pathways such as AMPK/mTOR, PI3K/AKT/mTOR, and Nrf2, which further modulate the cell cycle, autophagy, apoptosis, and tumor immunity [35,36].

Beginning with the concept of “multi-target antitumor” and progressing to “combination sensitization” and “clinical translation”, this review systematically examines the research advancements regarding natural products and drug repositioning in lung cancer [37,38]. This approach not only facilitates the summarization of their reproducible mechanisms of action but also aids in the identification of candidate molecules with significant development potential [15,16,39]. The review aims to delineate the challenges associated with lung cancer treatment, notable studies on natural products and the repurposing of approved drugs and strategies for combination therapy (Figure 1). The ultimate objective is to provide valuable references for subsequent basic research and clinical translation [31,40]. Furthermore, such studies may offer new insights for addressing critical clinical challenges, including drug resistance, relapse, and metastasis [28,32].

2. The Biological Basis and Research Entry Points of Lung Cancer Treatment

2.1. Classical Oncogenic Signaling Pathways and Therapeutic Tolerance

Common abnormal signaling networks in lung cancer include the PI3K/AKT/mTOR, MAPK/ERK, STAT3, Wnt/β-catenin, TGF-β, NF-κB, and Nrf2 pathways [41,42,43]. The distribution of these signaling pathways is shown in Table 1. The PI3K/AKT/mTOR pathway is closely linked to cell growth, protein synthesis, and metabolic maintenance [44,45,46,47,48,49]; The MAPK/ERK pathway is implicated in proliferation and survival signaling, while STAT3 is associated with inflammation, immunosuppression, and anti-apoptotic phenotypes [41,42,50]; Wnt/β-catenin, TGF-β, and NF-κB are commonly involved in epithelial-mesenchymal transition (EMT), invasion/metastasis, and therapy resistance [43,50]; Nrf2 serves as a key transcription factor that regulates cellular antioxidant defense and redox homeostasis [51,52], but it exhibits a dual role in tumors [35,53,54]. Numerous preclinical studies have indicated that these pathways represent common targets for natural active ingredients in the intervention of lung cancer [42,55,56].

2.2. Classification, Heterogeneity, and Therapeutic Challenges of Lung Cancer

Lung cancer is primarily classified into two major categories: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) [57,58], Among these, NSCLC predominantly encompasses lung adenocarcinoma, lung squamous cell carcinoma, and several other subtypes [59,60]. Different subtypes exhibit significant heterogeneity in driver gene profiles, immune microenvironments, metastatic propensity, and therapeutic sensitivity [61,62]. Driver gene alterations, such as EGFR, ALK, ROS1, KRAS, BRAF, and MET, present important opportunities for targeted therapy [63,64], However, the applicable patient population is limited, and the development of acquired resistance is nearly inevitable [57,65].

The development of drug resistance in lung cancer involves multiple mechanisms, including secondary mutations in the target and the activation of bypass pathways [66,67]. Additionally, epithelial-mesenchymal transition (EMT), lineage plasticity, upregulation of DNA repair mechanisms, and the enhancement of cancer stemness are also prevalent [68,69]. Under continuous therapeutic pressure, tumor cells can sustain survival by enhancing antioxidant defenses and remodeling metabolic-redox homeostasis [67,70,71]. Immune escape is particularly common in the context of immunotherapy resistance [72,73]. Consequently, single-target or single-agent strategies frequently fail to achieve long-term efficacy [74,75]. Therefore, the primary goal of this review is to delay the emergence of this drug resistance mechanism from the perspective of combined drug administration by reviewing recent research progress.

3. Antitumor Effects of Natural Products in Lung Cancer

3.1. Research Advantages of Natural Products

Natural products serve as a pivotal source for the discovery of antitumor drugs. Historically, numerous classic anticancer agents have been derived from natural products or their derivatives. In contrast to single-target synthetic drugs, natural products frequently exhibit more complex chemical structures and a wider array of biological activities, allowing them to exert a more comprehensive influence on various aspects of tumor initiation and progression. Specifically, the specific advantages and disadvantages of antitumor natural products compared with single-target antitumor drugs are shown in Table 2. Specifically for lung cancer, natural products are particularly effective in the following mechanisms of action: inducing programmed cell death, inhibiting tumor metabolic adaptation, suppressing migration and invasion, remodeling the tumor microenvironment, and enhancing sensitivity to radiotherapy, chemotherapy, and immunotherapy [76,77].

3.2. Anticancer Mechanisms of Natural Products

3.2.1. Induction of Apoptosis: A Classic but Still Important Pathway

Apoptosis evasion is a key reason for the sustained survival and treatment resistance of lung cancer cells. Natural products can promote programmed cell death in lung cancer cells by activating the mitochondrial pathway, death receptor pathway, and caspase cascade, thereby inhibiting tumor growth [78,79,80,81]. Additionally, this mechanism helps enhance the sensitivity of lung cancer cells to chemotherapy, radiotherapy, and targeted therapy, reducing the survival ability of residual cells after treatment [79,80,81,82].

3.2.2. Induced Autophagy and Cell Cycle Arrest

Lung cancer cells rely on abnormally active proliferation cycles and stress adaptation capabilities to sustain malignant growth [46,49]. Natural products can regulate autophagy levels, induce cell cycle arrest, block DNA replication and cell division processes, thereby inhibiting tumor proliferation [83]. This effect may also weaken the adaptability of lung cancer cells to the stress of chemotherapy and targeted therapy, enhancing the efficacy of combination therapy [84,85].

3.2.3. Inhibition of Migration, Invasion, and EMT

Invasion and distant metastasis are important causes of poor prognosis and treatment failure in lung cancer [86,87,88,89]. Natural products can reduce the invasive and metastatic potential of lung cancer cells by inhibiting EMT, decreasing cell motility, and impairing the ability to degrade the extracellular matrix [86,87,88,90]. This mechanism not only helps control disease progression but may also reduce the risk of tumor recurrence and metastasis following radiotherapy, chemotherapy, or targeted therapy [86,87,88,90].

3.2.4. Intervening in the Tumor Microenvironment

The tumor microenvironment provides lung cancer cells with immune evasion, angiogenesis, and drug resistance support [91,92]. Natural products can modulate immune cell functions, inflammatory cytokine release, angiogenesis, and extracellular matrix remodeling, thereby undermining the survival basis of lung cancer cells. This effect helps improve the immunosuppressive state and may enhance the overall efficacy of immunotherapy, chemotherapy, and radiotherapy [93,94,95,96].

3.2.5. Regulating Oxidative Stress and Mitochondrial Function

Lung cancer cells often exist in a state of abnormal oxidative stress and rely on mitochondria to maintain energy metabolism and resistance to cell death [5,97]. Natural products can disrupt redox balance, induce mitochondrial dysfunction, and promote cell death [97,98]. Since radiotherapy and certain chemotherapeutic agents are also closely associated with oxidative damage, this mechanism may enhance the sensitivity of lung cancer cells to radiotherapy and chemotherapy [15,97,99,100,101,102,103,104].

4. Research Progress on the Repurposing of Marketed Drugs in Lung Cancer

4.1. Value of Drug Repositioning

The primary advantage of drug repositioning lies in the established foundation of human safety, pharmacokinetics, and toxicology associated with existing medications. This generally leads to higher translational efficiency and shorter development cycles [105,106]. In comparison to entirely novel compounds, marketed drugs are more likely to progress to clinical reevaluation. For diseases such as lung cancer, which necessitate long-term treatment and often depend on combination regimens, drug repurposing is particularly advantageous for developing sensitizers, adjuvant therapies, or synergistic repositioning candidates within combination therapy. Nonetheless, it is crucial to reassess the dosage, toxicity, and drug interactions of older medications when applied to new indications [107,108,109].

4.2. Repositioning of Metabolic-Related Drug

Metformin is one of the most representative drugs in drug repurposing research. Originally used to treat type 2 diabetes, it has been shown to reshape energy metabolism in tumors and limit tumor cell growth by inhibiting mitochondrial complex I, reducing oxidative phosphorylation, activating AMPK, and downregulating mTOR signaling [110,111,112,113]. In the context of lung cancer, metformin not only has the potential to inhibit proliferation but also demonstrates synergistic effects when combined with chemotherapy, targeted therapy, or immunotherapy in preclinical and some early-stage clinical studies. However, existing randomized clinical evidence remains inconsistent, particularly in non-small cell lung cancer (NSCLC), where no stable conclusion regarding its benefits has yet been established [112,114]. Statins inhibit HMG-CoA reductase, interfere with the mevalonate pathway, and affect cholesterol synthesis and the stability of lipid rafts in the membrane [115]. This disruption impacts tumor cell signal transduction and membrane receptor function. Due to their role in cholesterol metabolism and the structural stability of membranes, statins are also considered to have potential anti-lung cancer effects [116,117].

4.3. Repurposing of Anti-Infective Drugs

Anti-infection-related marketed drugs represent a significant source for the repositioning of existing drugs in the treatment of lung cancer. Notably, chloroquine/hydroxychloroquine, itraconazole, artemisinin derivatives, and disulfiram have emerged as candidate drugs frequently explored in oncology research [118,119,120]. Among these, chloroquine and hydroxychloroquine are well-known for their mechanism of action, which involves the inhibition of lysosomal acidification and the blockade of autophagy flux. This action compromises the ability of tumor cells to adapt and survive under therapeutic stress [118,121]. Furthermore, itraconazole, beyond its antifungal properties, has been reported to exhibit antitumor activity and has the potential to reverse P-glycoprotein-mediated chemotherapy resistance in certain studies [5,120]. The relationship between artemisinin and its derivatives with reactive oxygen species (ROS) amplification, mitochondrial damage, and the induction of ferroptosis is well established. When combined with other sensitization strategies, these compounds can further enhance their antitumor effects [122,123,124]. The anticancer effects of disulfiram are primarily linked to copper-dependent ROS generation, inhibition of the NF-κB/ubiquitin-proteasome pathway, and modulation of tumor stemness and drug-resistant phenotypes. However, the clinical translation of disulfiram remains constrained by issues related to pharmacokinetic stability and inconsistent clinical benefits [39,58,119].

4.4. Neuropsychiatric and Other Drug Repurposing

Certain drugs originally developed for neuropsychiatric disorders, particularly specific antipsychotics, have demonstrated promising potential for drug repositioning in lung cancer research [125,126]. The phenothiazine drug trifluoperazine has been shown to inhibit DNA repair, delay the clearance of γH2AX following DNA damage, and impede cell cycle checkpoint recovery, thereby enhancing DNA damage-related cell death in a human non-small cell lung cancer model [106,126]. These effects are typically accompanied by elevated levels of reactive oxygen species (ROS), lysosomal dysfunction, vacuolization, and increased apoptosis. Although these ‘serendipitous discoveries’ may not necessarily represent the primary focus for clinical advancement, they provide valuable insights for anticancer drug screening and underscore the broad potential of drug repositioning [63,127].

5. Synergistic Mechanisms of Combination Therapy with Natural Products and Marketed Drugs

5.1. In Combination with Chemotherapy

The combination of natural products with conventional chemotherapeutic agents represents one of the most frequently explored and translationally promising modalities in the treatment of lung cancer [17,128]. The basic principle is not simply to increase toxicity; rather, it first weakens tumor cells to a certain extent through the use of natural products, below we show the details of the combination of some compounds in:

Ginsenoside Rg3: Natural ginsenoside Rg3 is a natural compound derived from ginseng (1, Figure 2). As one of the most abundant ginsenosides, it plays a significant role in preventing various cancers with minimal side effects [129,130]. This compound exhibits broad-spectrum anticancer activity, and its primary mechanisms include enhancing antioxidant and anti-inflammatory properties, regulating immune responses, inducing tumor cell apoptosis, inhibiting tumor invasion and metastasis, modulating tumor proliferation and angiogenesis, and reducing chemotherapy resistance and radioresistance [129,131]. Multiple clinical studies have shown that the combination of this compound with chemotherapy can provide multiple benefits in enhancing the anti-tumor efficacy, improving immune function, reducing chemotherapy toxicity, and inhibiting angiogenesis in patients with NSCLC, ultimately achieving improved disease control, prolonged overall survival, and enhanced quality of life [131,132]. It represents a promising adjuvant therapeutic option, but still requires further high-quality research for validation [133,134,135].

Matrine: Matrine is an alkaloid extracted from traditional Chinese herbs including Sophoraflavescentis, Sophora alopecuroides, Sophora root, etc. and exhibits a wide range of biological activities (3, Figure 2). Studies have shown that this compound can inhibit the growth of non-small cell lung cancer A549 cells, promote apoptosis, and inhibit cell migration, exerting a certain regulatory effect on lung cancer [136]. Multiple clinical studies have compared the efficacy of Matrine combined with platinum-based doublet chemotherapy (PBDC) versus PBDC alone in the treatment of advanced non-small cell lung cancer (NSCLC). The results indicated that the combination therapy improved the mean survival time (MST) and quality of life (QOL), while also reducing the incidence of adverse reactions compared with PBDC alone (p < 0.05). However, these conclusions need to be verified through strictly controlled randomized trials in the future before definitive conclusions can be drawn regarding this therapy [137,138].

Overall, the weakening pathways are diverse, such as inducing apoptosis of cancer cells (Ginsenoside Rg3, Artesunate, Honokiol), inhibiting angiogenesis (Honokiol), suppressing cancer cell migration (Matrine), and activating T cells (Carnosic Acid) through multiple mechanisms. We have presented in the Table 1 the research details of 6 natural products combined with chemotherapy for the regulation of lung cancer (1–6, Figure 2). Subsequently, this paves the way for platinum-based, taxane-based, or other chemotherapeutic agents to execute the primary cytotoxic effects. This strategy aims to enhance therapeutic efficacy while potentially reducing the required dosage of chemotherapy and improving patient tolerability [39,139].

Drug repositioning presents distinct advantages in this context. Metformin has been shown to enhance the sensitivity of tumor cells to chemotherapy through metabolic reprogramming. Additionally, chloroquine and hydroxychloroquine can diminish the buffering and adaptive capacities of tumor cells to chemotherapeutic stress by inhibiting autophagy [134,140].

Evidence from lung cancer studies indicates that autophagy inhibition can amplify the antitumor effects of topotecan and drugs related to the PI3K/mTOR pathway [141,142]. Furthermore, an early clinical study investigating the combination of hydroxychloroquine and erlotinib in advanced non-small cell lung cancer (NSCLC) supports its potential feasibility [143,144,145]. A large number of studies have combined these already marketed drugs with chemotherapy, but the results have not been encouraging. Metformin did not consistently improve PFS/OS in most studies [146,147] (8, Figure 2). HCQ/CQ, as autophagy inhibitors, can enhance chemotherapy sensitivity in experiments and a few clinical trials, but clinical outcomes have been inconsistent (7, 9, Figure 2). Overall, the effects of these combination therapies are not stable, and more clinical trial cases are needed for validation and exploration [148,149].

More broadly, certain marketed drugs with potential for repositioning can enhance the effects of chemotherapy by inducing oxidative stress, disrupting lysosomal function, or impairing DNA damage repair mechanisms. However, these effects are highly dependent on the specific drugs, dosages, and tumor backgrounds involved, and cannot be generalized as a universal characteristic of all anti-infective agents [150,151]. For patients with non-small cell lung cancer (NSCLC) who exhibit significant drug resistance, these combination regimens still require further biomarker-stratified studies [152,153,154].

Table 3. Detailed information on natural products and marketed drugs used in combination chemotherapy.

No	Compound	Sources	Mechanism	References
1	Ginsenoside Rg3	Panax ginseng	1) Improvement of antioxidant and anti-inflammation properties; 2) Immune regulation; 3) Induction of tumor apoptosis; 4) Prevention of tumor invasion and metastasis; 5) Reduction of chemoresistance and radioresistance.	[129]
2	Artesunate	semi-synthetic derivative of artemisinin	1) Alleviatiflammatory response; 2) Suppression of fibrosis; 3) Promotion of apoptosis	[39,155]
3	Matrine	The root bark of Sophora flavescens	1) Suppression of A549 cell migration; 2) Rduction of vascular endothelial growth factor A (VEGF-A) secretion in A549 cells	[136]
4	Carnosic Acid	The rosemary plant	1) Enhancement of CD8+ T cell lethality (suppression of MDSC by carnosic acid)	[156]
5	Resveratrol	A large variety of plant species	1) Inhibition of ADAM9 expression	[157]
6	Honokiol	Magnolia officinalis	1) promotion of cell cycle arrest; 2) Induction of apoptosis; 3) Inhibition of tumor growth, 4) Inhibition of angiogenesis and so on	[158]
7	Hydroxychloroquine	Synthetic analogs of quinine	1) uppression of autophagy	[148]
8	Metformin	Synthetic compounds	1) AMPK-dependent (direct) anticancer effects; 2) Selectively targeting cancer stem cells (CSCs); 3) Reversing multidrug resistance (MDR); 4) Inhibition of the metastasis of tumor	[147]
9	Chloroquine	Synthetic analogs of quinine	1) Uppression of autophagy	[149]

Table 3. Detailed information on natural products and marketed drugs used in combination chemotherapy.

No	Compound	Sources	Mechanism	References
1	Ginsenoside Rg3	Panax ginseng	1) Improvement of antioxidant and anti-inflammation properties; 2) Immune regulation; 3) Induction of tumor apoptosis; 4) Prevention of tumor invasion and metastasis; 5) Reduction of chemoresistance and radioresistance.	[129]
2	Artesunate	semi-synthetic derivative of artemisinin	1) Alleviatiflammatory response; 2) Suppression of fibrosis; 3) Promotion of apoptosis	[39,155]
3	Matrine	The root bark of Sophora flavescens	1) Suppression of A549 cell migration; 2) Rduction of vascular endothelial growth factor A (VEGF-A) secretion in A549 cells	[136]
4	Carnosic Acid	The rosemary plant	1) Enhancement of CD8+ T cell lethality (suppression of MDSC by carnosic acid)	[156]
5	Resveratrol	A large variety of plant species	1) Inhibition of ADAM9 expression	[157]
6	Honokiol	Magnolia officinalis	1) promotion of cell cycle arrest; 2) Induction of apoptosis; 3) Inhibition of tumor growth, 4) Inhibition of angiogenesis and so on	[158]
7	Hydroxychloroquine	Synthetic analogs of quinine	1) uppression of autophagy	[148]
8	Metformin	Synthetic compounds	1) AMPK-dependent (direct) anticancer effects; 2) Selectively targeting cancer stem cells (CSCs); 3) Reversing multidrug resistance (MDR); 4) Inhibition of the metastasis of tumor	[147]
9	Chloroquine	Synthetic analogs of quinine	1) Uppression of autophagy	[149]

5.2. Combination with Targeted Therapy

Targeted drugs are antitumor agents designed against specific gene mutations, protein targets, or signaling pathways unique to tumor cells. They can specifically identify and attack cancer cells while causing less damage to normal tissues. Compared with chemotherapy mentioned earlier, they offer advantages such as high selectivity, precise targeting, and fewer side effects. Currently, mainstream targeted drugs for lung cancer mainly act on driver genes such as EGFR, ALK, ROS1, MET, and KRAS. For example, Gefitinib (an EGFR-TKI), Osimertinib (a third-generation EGFR-TKI), and Crizotinib (an ALK-TKI) are all used in the treatment of lung cancer. Due to the inevitable emergence of drug resistance in lung cancer, which poses significant therapeutic challenges, there is an urgent need to explore new treatment strategies to overcome resistance. Natural compounds, with their inherent multi-target capabilities and favorable safety profiles, represent a promising approach to tackling this resistance. Below, we present some details on the application of natural products combined with targeted therapy. Additional details on more compounds are provided in Table 2 (1–6, Figure 3).

Curcumin: Curcumin is a polyphenolic compound derived from turmeric with broad anti-inflammatory and anticancer properties, effective against a variety of malignant tumors including colorectal cancer and oral cancer [159] (1, Figure 3). Numerous studies have explored its application in combination chemotherapy; for example, Curcumin has been shown to reverse cisplatin resistance in cisplatin-resistant lung cancer cells [160]. In terms of combination targeted therapy, the co-administration of Curcumin and Gefitinib can downregulate EGFR activity by inhibiting Sp1 and blocking the interaction between Sp1 and HDAC1, thereby significantly suppressing tyrosine kinase signaling as well as the ERK/MEK and AKT/S6K pathways in drug-resistant NSCLC cells [161]. Compared with Gefitinib or Curcumin alone, the combination treatment significantly induced autophagy, autophagic cell death, and autophagy-mediated apoptosis. These results indicate that the synergistic antitumor effect of Curcumin and Gefitinib is dependent on autophagy. Therefore, Curcumin may serve as a sensitizer to enhance the efficacy of EGFR-TKIs and overcome resistance to EGFR-TKIs in NSCLC patients harboring wild-type EGFR and/or KRAS mutations. Similarly, the combination of Curcumin and Erlotinib showed that this combined regimen could enhance cytotoxicity against Erlotinib-resistant NSCLC cells [162,163], promote Erlotinib-induced apoptosis, downregulate the expression of EGFR, p-EGFR, and Survivin, and inhibit NF-κB activation in drug-resistant NSCLC cells. In drug-resistant NSCLC cells, the pro-apoptotic effect of Curcumin combined with Erlotinib was comparable to that of Curcumin combined with Cisplatin. More importantly, the combination treatment of Curcumin and Erlotinib significantly inhibited tumor growth of Erlotinib-resistant NSCLC cells in vivo. Therefore, Curcumin is a potential adjuvant therapy for NSCLC patients during Erlotinib treatment [162].

Berberine: Berberine is an isoquinoline alkaloid derived from various Chinese herbal medicines [164] (2, Figure 3). Numerous studies have revealed its cardioprotective activity and broad-spectrum anticancer activity, covering multiple malignant tumors such as pancreatic cancer, cervical cancer, colorectal cancer, and breast cancer. Its anticancer mechanisms involve enhancing apoptosis and autophagy, inhibiting cell proliferation, regulating the cell cycle, impeding tumor cell migration, and inducing mitochondrial dysfunction, thereby affecting the survival and proliferation of lung cancer cells [165,166]. In studies investigating the combination therapy with Osimertinib, it was found that the co-administration of Berberine with Osimertinib effectively reversed the epithelial-mesenchymal transition (EMT) phenotype in Osimertinib-resistant non-small cell lung cancer (NSCLC) cells. This was specifically manifested as an upregulation of epithelial markers and a significant reduction in the levels of mesenchymal markers. This reversal of EMT contributes to overcoming Osimertinib resistance and enhancing treatment sensitivity. Additionally, the combination therapy significantly reduced the expression of Notch1 pathway-related components in drug-resistant cells, thereby inhibiting the activation of the Notch1 signaling pathway [166,167]. In summary, the combination of Berberine and Osimertinib can effectively eliminate the resistance of NSCLC cells to Osimertinib, providing a theoretical basis for future clinical research [166,168].

To date, there have been numerous studies investigating the combination of already marketed drugs with targeted therapy for the treatment of lung cancer. Drug repositioning offers a new research direction for overcoming resistance to targeted therapy in lung cancer [169,170,171]. Various older marketed drugs have been found to exhibit synergistic effects when combined with targeted agents such as EGFR-TKIs, particularly in EGFR-TKI-resistant NSCLC. Metformin is a representative metabolic repositioning drug that enhances the anti-lung cancer activity of Gefitinib, Erlotinib, or Osimertinib by activating AMPK, inhibiting mTOR/IGF-1R-related signaling, and regulating processes such as IL-6/STAT3 and EMT [172] (7, Figure 3). Old antimalarial/antirheumatic drugs represented by Hydroxychloroquine and Chloroquine mainly delay or reverse drug resistance by blocking the autophagy-lysosome pathway, attenuating EGFR-TKI-induced protective autophagy and drug-tolerant persister formation [173,174] (8–9, Figure 3). In addition, Celecoxib can enhance the inhibitory effect of gefitinib on NSCLC cells by inhibiting the COX-2/PGE2 axis and enhancing blockade of pathways such as AKT, ERK, and NF-κB [175] (10, Figure 3). More research details are described in the Table 2. These studies suggest that old drugs already on the market can provide candidate strategies for sensitizing targeted therapy and reversing drug resistance in lung cancer by modulating multiple mechanisms including metabolism, inflammation, autophagy, epigenetics, EMT, and bypass survival signaling [127,176]. It can also be foreseen that more old drugs will be invested in research on combination with targeted drugs for the treatment of lung cancer in the future [169,177,178,179].

Overall, at the molecular level, interfering with lung cancer progression and drug resistance through multiple signaling pathways has become a key entry point for research on the repurposing of natural products and marketed drugs [102,127,180]. It is important to emphasize that the core value of such strategies does not lie in the complete replacement of targeted drugs, but rather in delaying the evolution of resistance, improving the likelihood of sustained remission, and enhancing long-term efficacy through multi-pathway synergy [127,140,181]; However, at this stage, the evidence primarily derives from cellular and animal models, necessitating further validation through biomarker stratification, re-biopsy for drug resistance, and prospective combination trials [171,182,183].

Table 4. Detailed information on natural products and marketed drugs used in Targeted Therapy.

No	Compound	Sources	Mechanism	Combined Targeted Therapy	References
1	Curcumin	Herbal remedy and dietary spice turmeric	1). Inhibition of EGFR activity and its downstream MEK/ERK and AKT/S6K pathways (Gefitinib); 2). Downregulation of EGFR, p-EGFR and survivin, inhibition of NF-κB activation, and enhancement of erlotinib-induced apoptosis (Erlotinib)	Gefitinib; Erlotinib	[159,160,161,162,163]
2	Berberine	Medicinal plants such as Hydrastis canadensis, Berberis aristata, Coptis chinensis	1). Inhibition of MET kinase activity and downstream PI3K/AKT/mTOR and MEK/ERK signaling; 2). Upregulation of Bim, downregulation of Mcl-1, and promotion of apoptosis; 3). Inhibition of Notch1 signaling, reversal of EMT, and restoration of sensitivity to osimertinib	Osimertinib	[164,165,166]
3	Costunolide	Costus (Saussurea lappa Clarke) root	1). Dual inhibition of MEK1 and AKT1/2; 2). Blockade of ERK/RSK and AKT/GSK3β/NF-κB signaling	Osimertinib	[184,185,186]
4	Quercetin	From quercetum (oak forest)	1). Direct binding and inhibition of G6PD; 2). Reduction of NADPH levels; 3). Promotion of EGFR T790M protein degradation; 4). Consequent enhancement of gefitinib sensitivity	Gefitinib	[187,188]
5	Shikonin	Lithospermum erythrorhizon	1). Modulation of tumor energy metabolism, reduction of OCR and GlycoPER; downregulation of PKM2, p-EGFR, P-gp and HIF-1α, and increased intracellular accumulation of gefitinib	Gefitinib	[189,190]
6	Apigenin	Apium genus such as Chinese celery and parsley	1). Inhibition of HIF-1α, c-Myc and p-EGFR; 2). Reduction of GLUTs and MCT1 to disrupt glucose metabolism; blockade of autophagic flux and induction of apoptosis	Gefitinib	[191,192]
7	Metformin	Synthetic compound	1). Activation of AMPK and suppression of mTOR/IGF-1R-associated metabolic and growth signaling; 2). Inhibition of the IL-6/STAT3 axis, reversion of EMT; 3). Enhancement of EGFR-TKI-induced apoptosis	Gefitinib/Erlotinib/Icotinib/Osimertinib	[172]
8	Hydroxychloroquine	Synthetic analogs of quinine	1). Inhibition of lysosomal acidification and autophagic flux; 2). Attenuation of protective autophagy in tumor cells under EGFR-TKI stress	Erlotinib/Gefitinib	[173,174]
9	Chloroquine
10	Celecoxib	Synthetic compound	Inhibition of AKT and ERK pathways in NSCLC, as well as suppression of EGFR expression upon high-concentration treatment	Gefitinib	[175]
11	Loperamide	Synthetic compound	Enhancement of apoptosis and G1-phase cell cycle arrest	Gefitinib	[193]
12	Flunarizine	Synthetic compound	Upregulation of the pro-apoptotic protein Bim and the cell cycle inhibitor p27Kip1, and downregulation of Bcl-2	Gefitinib	[194]
13	Lymecycline	Synthetic compound	1). Inhibition of EGFR phosphorylation and its downstream AKT/ERK/STAT3 signaling; 2). Induction of cell cycle arrest and apoptosis	Icotinib	[195]
14	Doxazosin	Synthetic compound	1). Induction of cytotoxic autophagy	Osimertinib	[196]
15	Thioridazine	Synthetic compound	1). Reduction of p-AKT levels and promotion of apoptosis	Gefitinib	[197]
16	Glimepiride	Synthetic compound	1). Activation of AMPK followed by suppression of ERK/MMP7 signaling	EGFR-TKIs	[198]

Table 4. Detailed information on natural products and marketed drugs used in Targeted Therapy.

No	Compound	Sources	Mechanism	Combined Targeted Therapy	References
1	Curcumin	Herbal remedy and dietary spice turmeric	1). Inhibition of EGFR activity and its downstream MEK/ERK and AKT/S6K pathways (Gefitinib); 2). Downregulation of EGFR, p-EGFR and survivin, inhibition of NF-κB activation, and enhancement of erlotinib-induced apoptosis (Erlotinib)	Gefitinib; Erlotinib	[159,160,161,162,163]
2	Berberine	Medicinal plants such as Hydrastis canadensis, Berberis aristata, Coptis chinensis	1). Inhibition of MET kinase activity and downstream PI3K/AKT/mTOR and MEK/ERK signaling; 2). Upregulation of Bim, downregulation of Mcl-1, and promotion of apoptosis; 3). Inhibition of Notch1 signaling, reversal of EMT, and restoration of sensitivity to osimertinib	Osimertinib	[164,165,166]
3	Costunolide	Costus (Saussurea lappa Clarke) root	1). Dual inhibition of MEK1 and AKT1/2; 2). Blockade of ERK/RSK and AKT/GSK3β/NF-κB signaling	Osimertinib	[184,185,186]
4	Quercetin	From quercetum (oak forest)	1). Direct binding and inhibition of G6PD; 2). Reduction of NADPH levels; 3). Promotion of EGFR T790M protein degradation; 4). Consequent enhancement of gefitinib sensitivity	Gefitinib	[187,188]
5	Shikonin	Lithospermum erythrorhizon	1). Modulation of tumor energy metabolism, reduction of OCR and GlycoPER; downregulation of PKM2, p-EGFR, P-gp and HIF-1α, and increased intracellular accumulation of gefitinib	Gefitinib	[189,190]
6	Apigenin	Apium genus such as Chinese celery and parsley	1). Inhibition of HIF-1α, c-Myc and p-EGFR; 2). Reduction of GLUTs and MCT1 to disrupt glucose metabolism; blockade of autophagic flux and induction of apoptosis	Gefitinib	[191,192]
7	Metformin	Synthetic compound	1). Activation of AMPK and suppression of mTOR/IGF-1R-associated metabolic and growth signaling; 2). Inhibition of the IL-6/STAT3 axis, reversion of EMT; 3). Enhancement of EGFR-TKI-induced apoptosis	Gefitinib/Erlotinib/Icotinib/Osimertinib	[172]
8	Hydroxychloroquine	Synthetic analogs of quinine	1). Inhibition of lysosomal acidification and autophagic flux; 2). Attenuation of protective autophagy in tumor cells under EGFR-TKI stress	Erlotinib/Gefitinib	[173,174]
9	Chloroquine
10	Celecoxib	Synthetic compound	Inhibition of AKT and ERK pathways in NSCLC, as well as suppression of EGFR expression upon high-concentration treatment	Gefitinib	[175]
11	Loperamide	Synthetic compound	Enhancement of apoptosis and G1-phase cell cycle arrest	Gefitinib	[193]
12	Flunarizine	Synthetic compound	Upregulation of the pro-apoptotic protein Bim and the cell cycle inhibitor p27Kip1, and downregulation of Bcl-2	Gefitinib	[194]
13	Lymecycline	Synthetic compound	1). Inhibition of EGFR phosphorylation and its downstream AKT/ERK/STAT3 signaling; 2). Induction of cell cycle arrest and apoptosis	Icotinib	[195]
14	Doxazosin	Synthetic compound	1). Induction of cytotoxic autophagy	Osimertinib	[196]
15	Thioridazine	Synthetic compound	1). Reduction of p-AKT levels and promotion of apoptosis	Gefitinib	[197]
16	Glimepiride	Synthetic compound	1). Activation of AMPK followed by suppression of ERK/MMP7 signaling	EGFR-TKIs	[198]

5.3. Combined with Radiotherapy

Radiotherapy primarily relies on ionizing radiation to induce DNA double-strand breaks, which are accompanied by the accumulation of reactive oxygen species (ROS), thereby triggering tumor cell death. However, tumor cells often develop radioresistance through mechanisms such as the Nrf2-driven antioxidant network, the GSH-GPX4 axis, and enhanced DNA damage repair capacity [199,200,201,202]. Therefore, natural products and existing drugs that can amplify oxidative stress, deplete GSH, inhibit Nrf2 signaling, or interfere with DNA repair present a theoretical basis for their use as radiosensitizers [201,202,203].

In recent years, a variety of natural products and their derivative preparations have been explored for strategies to enhance radiosensitivity in lung cancer radiotherapy. β-Elemene can increase the sensitivity of NSCLC to ionizing radiation/X-ray irradiation by inhibiting EMT, cancer stemness, and the Prx-1/NF-κB/iNOS signaling axis, as well as enhancing DNA damage and inhibiting Rad51-associated repair [204] (1, Figure 4). Myricetin and quercetin, as flavonoids, enhance the sensitivity of lung cancer cells to X-ray irradiation by promoting Caspase-3-related apoptosis and regulating the miR-16-5p/WEE1 axis, respectively [188,205,206,207,208] (2–3, Figure 4). Details are provided in the Table 3.

Drug repositioning of the same drugs has provided new research directions for radiosensitization in lung cancer [17,209,210]. Multiple already-marketed old drugs have been reassessed as radiation sensitizers, including the anti-HIV drug nelfinavir (5, Figure 4), the antidiabetic drug metformin (6, Figure 4), the COX-2 inhibitor celecoxib (7, Figure 4), the anthelmintic drug niclosamide (8, Figure 4), the lipid-lowering drugs statins, the autophagy inhibitors chloroquine/hydroxychloroquine, and the anti-alcoholism drug disulfiram (11, Figure 4), among others. Nelfinavir is a case with relatively sufficient clinical translational evidence. Its combination with external-beam thoracic radiotherapy or concurrent chemoradiotherapy for unresectable locally advanced NSCLC may enhance the effect of radiotherapy by inhibiting PI3K/AKT, downregulating HIF-1α/VEGF, and improving tumor oxygenation [211]. Metformin, as a metabolic old drug, has also been studied in concurrent chemoradiotherapy for locally advanced NSCLC (6, Figure 4). However, the randomized phase II OCOG-ALMERA trial did not show clear benefit, suggesting that its clinical application still requires further biomarker screening and population optimization [212,213]. At the preclinical level, niclosamide can reverse acquired radioresistance in lung cancer by blocking the JAK2/STAT3/Bcl-2/Bcl-XL pathway [214,215] (8, Figure 4); Celecoxib can enhance the killing effect of X-ray irradiation by inhibiting COX-2/PGE2 and EGFR nuclear translocation/DNA-PK-mediated DNA repair [216,217] (7, Figure 4); statins such as lovastatin and atorvastatin increase the sensitivity of lung cancer cells to ionizing radiation by affecting the mevalonate pathway, AKT/AMPK, ROS, and apoptosis [218,219,220,221,222] (9–10, Figure 4). These studies suggest that already marketed old drugs can enhance the efficacy of radiotherapy for lung cancer through mechanisms such as metabolic regulation, DNA repair inhibition, hypoxia improvement, autophagy blockade, and immune microenvironment remodeling. However, except for a few drugs that have undergone early clinical studies, most are still in the preclinical stage [200,202,203]. In addition to monomeric compounds, there are also compound formulations. For example, S-1 (Tegafur/Gimeracil/Oteracil) is an oral anticancer compound formulation composed of three synthetic small molecules precisely proportioned, which also exerts anticancer effects when used in combination with radiotherapy [223].

Table 5. Detailed information on natural products and marketed drugs used in Radiotherapy.

No	Compound	Sources	Mechanism	Combined Radiotherapy	References
1	β-Elemene	Curcuma wenyujin	1). Inhibition of EMT and CSC phenotypes; 2). Suppression of the Prx-1/NF-κB/iNOS signaling axis	Ionizing radiation/X-ray irradiation	[204]
2	Myricetin	Many natural plants	1). Upregulation of Caspase-3; 2). Promotion of radiation-induced apoptosis	X-ray irradiation	[205,206]
3	Quercetin	Fruits and vegetables	1). Upregulation of miR-16-5p, inhibition of WEE1, disruption of the G2/M checkpoint and suppression of radioresistance	X-ray irradiation	[188,207]
4	Linebacker-1	NP-derived semisynthetic drug	1). Promotion of radiation-induced apoptosis	IGRT/X-ray irradiation	[208]
5	Nelfinavir	Synthetic compound	1). Inhibition of the PI3K/AKT survival pathway; 2). Downregulation of HIF-1α/VEGF, improvement of tumor oxygenation, and reduction of hypoxia-associated radioresistance	External-beam thoracic radiotherapy; 3D conformal radiotherapy, 3D-CRT; intensity-modulated radiotherapy, IMRT	[211]
6	Metformin	Synthetic compound	1). Activation of AMPK, inhibition of mTOR and suppression of tumor metabolic adaptation	Concurrent external-beam thoracic radiotherapy/concurrent chemoradiotherapy	[212,213]
7	Celecoxib	Synthetic compound	1). Inhibition of the pro-inflammatory and pro-survival COX-2/PGE2 axis; 2). Enhancement of apoptosis and cell cycle arrest	X-ray irradiation/ionizing radiation	[216,217]
8	Niclosamide	Synthetic compound	1). Inhibition of the JAK2/STAT3/Bcl-2/Bcl-XL survival pathway and reduction of STAT3 nuclear localization; 2). Blockade of anti-apoptotic signals and restoration of radiotherapy-induced cell death	Ionizing radiation/X-ray irradiation	[214,215]
9	Lovastatin	Aspergillus terreus	1). Reduction of EGFR/AKT-associated survival signals; concurrent enhancement of AMPK phosphorylation and induction of apoptosis	Ionizing radiation	[218,219]
10	Atorvastatin	Synthetic compound	1). Augmentation of ROS production, promotion of apoptosis and radiation-induced cell death	Ionizing radiation	[220]
11	Disulfiram	Synthetic compound	1). Potential regulation of radiosensitivity via the NF-κB pathway; 2). oncurrent upregulation of PD-L1 and remodeling of the post-radiation tumor immune microenvironment	Ionizing radiation	[224]

Table 5. Detailed information on natural products and marketed drugs used in Radiotherapy.

No	Compound	Sources	Mechanism	Combined Radiotherapy	References
1	β-Elemene	Curcuma wenyujin	1). Inhibition of EMT and CSC phenotypes; 2). Suppression of the Prx-1/NF-κB/iNOS signaling axis	Ionizing radiation/X-ray irradiation	[204]
2	Myricetin	Many natural plants	1). Upregulation of Caspase-3; 2). Promotion of radiation-induced apoptosis	X-ray irradiation	[205,206]
3	Quercetin	Fruits and vegetables	1). Upregulation of miR-16-5p, inhibition of WEE1, disruption of the G2/M checkpoint and suppression of radioresistance	X-ray irradiation	[188,207]
4	Linebacker-1	NP-derived semisynthetic drug	1). Promotion of radiation-induced apoptosis	IGRT/X-ray irradiation	[208]
5	Nelfinavir	Synthetic compound	1). Inhibition of the PI3K/AKT survival pathway; 2). Downregulation of HIF-1α/VEGF, improvement of tumor oxygenation, and reduction of hypoxia-associated radioresistance	External-beam thoracic radiotherapy; 3D conformal radiotherapy, 3D-CRT; intensity-modulated radiotherapy, IMRT	[211]
6	Metformin	Synthetic compound	1). Activation of AMPK, inhibition of mTOR and suppression of tumor metabolic adaptation	Concurrent external-beam thoracic radiotherapy/concurrent chemoradiotherapy	[212,213]
7	Celecoxib	Synthetic compound	1). Inhibition of the pro-inflammatory and pro-survival COX-2/PGE2 axis; 2). Enhancement of apoptosis and cell cycle arrest	X-ray irradiation/ionizing radiation	[216,217]
8	Niclosamide	Synthetic compound	1). Inhibition of the JAK2/STAT3/Bcl-2/Bcl-XL survival pathway and reduction of STAT3 nuclear localization; 2). Blockade of anti-apoptotic signals and restoration of radiotherapy-induced cell death	Ionizing radiation/X-ray irradiation	[214,215]
9	Lovastatin	Aspergillus terreus	1). Reduction of EGFR/AKT-associated survival signals; concurrent enhancement of AMPK phosphorylation and induction of apoptosis	Ionizing radiation	[218,219]
10	Atorvastatin	Synthetic compound	1). Augmentation of ROS production, promotion of apoptosis and radiation-induced cell death	Ionizing radiation	[220]
11	Disulfiram	Synthetic compound	1). Potential regulation of radiosensitivity via the NF-κB pathway; 2). oncurrent upregulation of PD-L1 and remodeling of the post-radiation tumor immune microenvironment	Ionizing radiation	[224]

5.4. Combination with Immunotherapy

Immune checkpoint inhibitors have emerged as a crucial cornerstone in the treatment of advanced non-small cell lung cancer (NSCLC) [93,105,225,226]. However, their overall response rate remains limited, and their efficacy is significantly influenced by the tumor immune microenvironment, PD-L1 expression status, and antigen presentation capacity [227,228,229]. Consequently, natural products and drug repositioning molecules that can remodel the immune microenvironment are increasingly recognized as promising candidates for combination immunotherapy [230,231,232,233,234].

In recent years, natural products have been widely used to explore strategies for sensitizing lung cancer immunotherapy, with a particular focus on enhancing the efficacy of immunotherapy and reversing immunotherapy resistance [230,232,233,235]. Ginsenosides are representative natural products [236,237], among which Ginsenoside Rb1 (2, Figure 5), when delivered via TMTP1 peptide-enhanced exosomes, can enhance the efficacy of nivolumab in a PI3K-mutated NSCLC model of acquired immunotherapy resistance. The underlying mechanism involves inhibition of the PI3K/AKT/mTOR pathway, promotion of M1 macrophage polarization, and enhancement of CD8+ T cell proliferation and cytotoxicity [238,239,240]. Ginsenoside F3 alleviates T cell exhaustion via RIPOR2-mediated immunometabolic reprogramming, enhancing anti-PD-1 therapy in a mouse model of NSCLC [241] (3, Figure 5). In addition to ginsenosides, andrographolide can enhance anti-PD-1 therapy by suppressing the COX2/PGE2 immunosuppressive axis, and promote CD8+ T cell infiltration and functional recovery [242,243] (1, Figure 5). Furthermore, resveratrol-related nanoformulations and derivatives can enhance the immunotherapy response in lung cancer by improving CD8+ T cell metabolism or inhibiting the JAK2-PD-1/PD-L1 axis [244,245] (12, Figure 5). Please refer to Figure 5 for more details.

The combination of marketed drugs and immune checkpoint inhibitors provides an important strategy for drug repurposing and rapid translation in lung cancer treatment [228,230,231,246,247]. Current studies have shown that marketed single drugs capable of synergizing with immunotherapy are primarily concentrated in categories such as anti-angiogenic drugs, DNA damage repair inhibitors, transcription-inhibitory cytotoxic drugs, and inflammatory pathway modulators. Anti-angiogenic drugs represent one of the most well-evidenced directions; for example, the combination of Bevacizumab and Atezolizumab can improve tumor vascular abnormalities and immunosuppressive microenvironment through VEGF-A blockade, promote T cell infiltration, and show potential advantages in non-squamous NSCLC, especially in the context of immunosuppression associated with liver metastases [227,228,229,248,249,250]. On the other hand, the combination of PARP inhibitors Niraparib or Olaparib with Pembrolizumab/Durvalumab represents a synergistic approach between DNA damage response inhibition and immune checkpoint blockade, with mechanistic bases including DNA damage accumulation, enhanced tumor immunogenicity, and regulation of PD-L1 expression [251,252,253] (10–11, Figure 5); however, results from studies such as KEYLYNK-006 suggest that such mechanistically rational combinations do not necessarily translate into clear survival benefits [254]. In SCLC, the maintenance therapy combination of Lurbinectedin and Atezolizumab further expands the application scenarios of combining marketed drugs with immunotherapy [255,256,257] (8, Figure 5). The underlying basis is that Lurbinectedin can induce immunogenic cell death, thereby promoting antigen release and antitumor immune responses [255,256,257]. Therefore, the combination of marketed single drugs with immunotherapy represents an important direction for optimizing lung cancer treatment. However, its success depends on a clear mechanistic basis, appropriate disease context, and biomarker-guided patient selection.

Table 5. Detailed information on natural products and marketed drugs used in Immunotherapy.

No	Compound	Sources	Mechanism	Combined Immunotherapy	References
1	Andrographolide	Andrographis paniculata	1). Inhibition of COX2 activity and PGE2 release, alleviation of PGE2-mediated immunosuppression	Anti-PD-1 antibody	[242,243]
2	Ginsenoside Rb1	Panax ginseng	1). Inhibition of the PI3K/AKT/mTOR pathway; 2). Promotion of M1 macrophage polarization	Nivolumab/anti-PD-1 therapy	[238,239,240]
3	Ginsenoside F3	Panax ginseng	1). Restoration of RIPOR2-mediated immunometabolic regulation for alleviation of T cell exhaustion	Anti-PD-1 therapy	[241]
4	RVX-208	Resveratrol derivative	1). Interference with JAK2 phosphorylation; 2). Reduction of PD-1 expression in T lymphocytes and PD-L1 expression in lung cancer cells	Anti-PD-1 antibody	[245]
5	Ginsenoside Rg3	Panax ginseng	1). Inhibition of PD-L1 glycosylation; 2). promotion of PD-L1 destabilization or reduction of functional PD-L1, thereby restoration of T cell-mediated cytotoxicity	Atezolizumab	[236,237]
6	Myricetin	Many plants	1). Inhibition of the JAK-STAT-IRF1 pathway and reduction of PD-L1 and IDO1 expression	PD-1/PD-L1 blockade	[258,259]
7	Nagilactone E	Podocarpus nagi	1). Upregulation of PD-L1 via the JNK-c-Jun axis, enhancement of tumor reliance on the PD-1/PD-L1 immune evasion pathway	PD-L1 inhibitors	[260]
8	Lurbinectedin	Synthetic derivative	1). DNA-binding transcriptional inhibitor with capacities of DNA damage and transcriptional stress induction	Atezolizumab	[255,256,257]
9	Anlotinib	Synthetic derivative	1). Inhibition of VEGFR, FGFR, PDGFR and related signaling pathways	Sintilimab	[254]
10	Niraparib	Synthetic derivative	1). Niraparib-mediated inhibition of PARP-dependent single-strand DNA damage repair	Pembrolizumab	[251]
11	Olaparib	Synthetic derivative	1). Olaparib-mediated inhibition of PARP1/2 potentiates DNA damage and replication stress	Pembrolizumab	[252,253]
12	Resveratrol	Many plants	1). Targeting of CD93 for modulation of the CD93–AKT–PAK5–AIF axis; 2). Promotion of AIF mitochondrial translocation	Anti-PD-1 therapy	[244]
13	Bevacizumab	Recombinant humanized IgG1κ monoclonal antibody	1). Blockade of VEGF-A for the inhibition of aberrant angiogenesis and promotion of vascular normalization	Atezolizumab	[248,249,250]
14	Canakinumab	Recombinant humanized monoclonal antibody	1). High-affinity anti-IL-1β monoclonal antibody canakinumab	Pembrolizumab	[261]

Table 5. Detailed information on natural products and marketed drugs used in Immunotherapy.

No	Compound	Sources	Mechanism	Combined Immunotherapy	References
1	Andrographolide	Andrographis paniculata	1). Inhibition of COX2 activity and PGE2 release, alleviation of PGE2-mediated immunosuppression	Anti-PD-1 antibody	[242,243]
2	Ginsenoside Rb1	Panax ginseng	1). Inhibition of the PI3K/AKT/mTOR pathway; 2). Promotion of M1 macrophage polarization	Nivolumab/anti-PD-1 therapy	[238,239,240]
3	Ginsenoside F3	Panax ginseng	1). Restoration of RIPOR2-mediated immunometabolic regulation for alleviation of T cell exhaustion	Anti-PD-1 therapy	[241]
4	RVX-208	Resveratrol derivative	1). Interference with JAK2 phosphorylation; 2). Reduction of PD-1 expression in T lymphocytes and PD-L1 expression in lung cancer cells	Anti-PD-1 antibody	[245]
5	Ginsenoside Rg3	Panax ginseng	1). Inhibition of PD-L1 glycosylation; 2). promotion of PD-L1 destabilization or reduction of functional PD-L1, thereby restoration of T cell-mediated cytotoxicity	Atezolizumab	[236,237]
6	Myricetin	Many plants	1). Inhibition of the JAK-STAT-IRF1 pathway and reduction of PD-L1 and IDO1 expression	PD-1/PD-L1 blockade	[258,259]
7	Nagilactone E	Podocarpus nagi	1). Upregulation of PD-L1 via the JNK-c-Jun axis, enhancement of tumor reliance on the PD-1/PD-L1 immune evasion pathway	PD-L1 inhibitors	[260]
8	Lurbinectedin	Synthetic derivative	1). DNA-binding transcriptional inhibitor with capacities of DNA damage and transcriptional stress induction	Atezolizumab	[255,256,257]
9	Anlotinib	Synthetic derivative	1). Inhibition of VEGFR, FGFR, PDGFR and related signaling pathways	Sintilimab	[254]
10	Niraparib	Synthetic derivative	1). Niraparib-mediated inhibition of PARP-dependent single-strand DNA damage repair	Pembrolizumab	[251]
11	Olaparib	Synthetic derivative	1). Olaparib-mediated inhibition of PARP1/2 potentiates DNA damage and replication stress	Pembrolizumab	[252,253]
12	Resveratrol	Many plants	1). Targeting of CD93 for modulation of the CD93–AKT–PAK5–AIF axis; 2). Promotion of AIF mitochondrial translocation	Anti-PD-1 therapy	[244]
13	Bevacizumab	Recombinant humanized IgG1κ monoclonal antibody	1). Blockade of VEGF-A for the inhibition of aberrant angiogenesis and promotion of vascular normalization	Atezolizumab	[248,249,250]
14	Canakinumab	Recombinant humanized monoclonal antibody	1). High-affinity anti-IL-1β monoclonal antibody canakinumab	Pembrolizumab	[261]

6. Delivery Systems and Formulation Optimization

Although natural products and certain marketed drugs demonstrate significant preclinical antitumor potential for lung cancer treatment, their clinical application is frequently hindered by pharmaceutical limitations, including poor water solubility, inadequate in vivo exposure, nontargeted distribution, and rapid metabolic clearance [262,263,264]. To mitigate these challenges, various strategies have emerged, such as the use of nanoparticles, liposomes, exosomes/extracellular vesicles (EVs), polymeric micelles, stimuli-responsive carriers, and multi-drug co-delivery systems, which aim to enhance drug delivery efficiency and tissue selectivity in vivo [264,265,266,267].

The advantages of nanodelivery systems are primarily reflected in three key aspects [268,269,270]. First, they can significantly enhance the apparent solubility, dispersibility, and physicochemical stability of hydrophobic drugs [154,271]; Second, they improve in vivo exposure by prolonging circulation time, reducing non-specific clearance, and enhancing tumor accumulation [183,272,273]. Third, they facilitate synergistic co-delivery, sequential drug release, and on-demand responses to the tumor microenvironment [264,274,275]. In the case of natural products, delivery systems not only improve bioavailability but also enhance cellular uptake, tissue distribution, and pharmacodynamic performance [64,151,270], thereby increasing their potential as anti-tumor candidates [262,264,276]. Regarding the repositioning strategy for marketed drugs, formulation optimization can address previous limitations in tissue distribution, narrow therapeutic windows, and systemic toxicity [277], while improving their feasibility as components of combination therapy [275,278,279]. In the context of lung cancer, local delivery, inhalation administration, targeted release, and responsive release designs that account for tumor microenvironment characteristics—such as acidity, hypoxia, and redox imbalance—are expected to increase local drug exposure at the lesion site and reduce systemic toxicity [180,183,280,281], representing a significant direction for future optimization of delivery systems [263,282,283,284].

Despite the low immunogenicity and favorable biocompatibility of exosomes/extracellular vesicles (EVs), several challenges persist in their isolation and purification, ensuring batch-to-batch consistency, achieving standardized production, and enhancing drug loading efficiency [269,270,285]. Consequently, they are better characterized as “platforms with translational potential” [134,286], rather than “already mature delivery tools” [281,287,288,289]. Moving forward, the optimization of delivery systems for lung cancer should further incorporate materials engineering, localized drug administration, biomarker stratification, and the design of combination therapies to create a translational pathway that effectively balances efficacy, safety, and manufacturability [275,278,282].

7. Clinical Translation: Current Status and Challenges

Although natural products and the repurposing of approved drugs have demonstrated significant preclinical antitumor activity in lung cancer [225,290], the transition from basic research to clinical application continues to encounter several challenges [226,291,292]. Firstly, many studies remain confined to in vitro cell experiments, lacking adequate in vivo pharmacodynamics, pharmacokinetics, and toxicology validation [292,293]. econdly, natural products are derived from complex sources and exhibit considerable variation in composition and batch; without standardized preparation and quality control, their reproducibility of results and comparability across studies may be compromised [128,294,295]. A Furthermore, while combination therapeutic strategies theoretically provide advantages in synergistic sensitization and overcoming drug resistance, their clinical translation necessitates systematic optimization of drug ratios, administration sequences, timing, and toxicity thresholds [58,292,294]. Additionally, lung cancer patients display significant heterogeneity in molecular typing and tumor microenvironments [296,297]. Therefore, future research should prioritize biomarker stratification to identify patient subgroups most likely to benefit from combination regimens involving natural products or drug repurposing [128,293,298].

At the methodological level, patient-derived organoids and patient-derived xenograft (PDX) models, along with multi-omics analysis and real-world data, can provide complementary evidence for clinical translation [44,141,247]; Among these, organoids and PDX models are particularly suitable for functional drug sensitivity verification and mechanistic studies, while clinical cohorts and real-world data enhance extrapolability and clinical relevance [292,293,299].

8. Conclusions

Overall, natural product research and the repurposing of approved drugs represent two complementary yet pragmatic development pathways in the field of lung cancer therapy. Natural products, derived from abundant biological resources, exhibit structural diversity and target a wide range of action mechanisms, often revealing novel modes of action and offering the potential to address existing therapeutic bottlenecks. In contrast, drug repurposing capitalizes on the established clinical safety profiles, shortened development timelines, and high translational efficiency of approved drugs, facilitating rapid advancement to clinical application. This strategy is particularly well-suited to tackle clinical challenges such as the significant heterogeneity and susceptibility to drug resistance observed in lung cancer. These two pathways converge significantly in their intervention within the lung cancer survival network—both can modulate tumor proliferation, apoptosis, metabolism, and epigenetic status through a multitarget, multipathway regulatory framework, particularly demonstrating substantial potential for synergistic enhancement in emerging research areas such as ferroptosis, metabolic reprogramming, and epigenetic regulation.