Immunotherapy for Cutaneous Squamous Cell Carcinoma in Aging Societies: Clinical Evidence and Geriatric Oncology Considerations

1. Introduction

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer worldwide. Its incidence has been increasing in parallel with population aging, particularly among individuals aged ≥65 years [1,2]. Striking geographic and ethnic disparities exist: the incidence is 270 per 100,000 person-years in Australia [3] but remains significantly lower in East Asia (e.g., approximately 3–4 per 100,000 in Japan) [4]. However, rapidly aging societies in East Asia are now experiencing a disproportionate increase in disease burden; for instance, the incidence of cSCC nearly doubled between 1999 and 2019 [5].

In Japan, nationwide registry data have confirmed that cSCC accounts for approximately 44% of all skin cancers, with a particularly sharp increase among the older population [4]. Furthermore, clinical data have demonstrated that patients aged ≥90 years represent a substantial and growing subgroup: in a multicenter surgical series, one-third of all cSCC cases occurred in nonagenarians, who exhibited significantly higher recurrence risk despite standard treatment [6]. Although cSCC generally has a lower case-fatality rate than that of melanoma, its burden in older adults is substantial; for example, the disability-adjusted life-year rate in the 70–74-year age group is approximately 74.59 per 100,000 population, underscoring its significant impact in aging societies [7]. These epidemiological observations highlight the urgent need to adapt cSCC management strategies to the realities of super-aged societies, particularly in East Asia, while recognizing the regional and ethnic disparities in incidence and outcomes. Therefore, a deeper understanding of the biological mechanisms underlying cSCC development is essential. In particular, age-associated changes in the immune system, commonly referred to as immunosenescence, play a critical role in both the pathogenesis of cSCC and the response to emerging therapies, such as programmed cell death protein 1 (PD-1) inhibitors. Accordingly, this review focuses on the age- and region-specific challenges of cSCC management in older patients in East Asia, with a particular emphasis on frailty, comorbid conditions, and the safe use of immunotherapy in Japan’s super-aged society, where local data remain limited.

2. Biology and Risk Factors Relevant to Cutaneous Squamous Cell Carcinoma (cSCC) in the Older Population

cSCC predominantly affects older adults, and the aging immune system (“immunosenescence”) can influence both tumor behavior and treatment outcomes. Immunosenescence is the progressive decline in immune function with age and is characterized by systemic changes that foster tumor immune evasion [8]. This section explores key age-related immunological changes, including T-cell dysfunction, altered antigen presentation, accumulation of suppressive cells, and inflammatory shifts, and how they affect the efficacy and safety of PD-1 inhibitor immunotherapy in cSCC. We draw on evidence from cSCC and related cancers to highlight the tumor microenvironment (TME) in older patients and the clinical outcomes of immune checkpoint blockade in older patients.

2.1. Immunosenescence: Age-Related Immune Changes

Aging is associated with broad immune remodeling, which can impair antitumor immunity. Thymic involution and bone marrow changes lead to reduced naive T-cell output, skewing toward memory and senescent T-cell populations [9,10,11]. Thus, older individuals have fewer fresh T cells that respond to new antigens and more terminally differentiated or exhausted T cells. Aged T cells often upregulate inhibitory receptors, such as PD-1, T-cell immunoglobulin and mucin-domain containing-3, and lymphocyte activation gene-3 [12]. These age-related immune alterations may affect the responsiveness and toxicity profiles of immune checkpoint inhibitors (ICIs) in older adults [13], reflecting a state of chronic stimulation and T-cell exhaustion. Functionally, older T cells exhibit a diminished proliferative capacity and impaired cytotoxicity [14]. In parallel, age-associated defects in antigen-presenting cells (APCs), including dendritic cells, result in reduced costimulatory activity, which may compromise the efficient priming of T-cell responses [14]. The cytotoxic function of natural killer cells also declines with age [14], further limiting the ability of the innate immune system to control tumors.

Immunosenescence is also marked by myeloid skewing of hematopoiesis, leading to increased production of myeloid cells at the expense of lymphoid cells [15]. This can translate into higher levels of immunosuppressive myeloid-derived suppressor cells (MDSCs) and M2-polarized macrophages in older individuals, which actively dampen T-cell responses in the TME [16]. Additionally, aging tissues accumulate senescent cells (e.g., fibroblasts) that secrete pro-tumor and immunosuppressive factors, such as the senescence-associated secretory phenotype. These factors (including interleukin [IL]-6, IL-1 family cytokines, tumor growth factor [TGF]-β) drive chronic low-grade inflammation, a phenomenon termed “inflammaging” [16,17]. Inflammaging sustains a proinflammatory milieu that paradoxically contributes to immune dysregulation, recruits immune cells in a dysfunctional manner, and promotes the accumulation of suppressive populations. For example, regulatory T cells (Tregs; CD4⁺FOXP3⁺), which restrain antitumor immunity, increase in frequency with age in mice and in certain human tissues [18]. Conversely, the pool of antigen-specific effector T cells may be present in normal numbers in an aged host but fail to migrate into peripheral tissue efficiently. Notably, older individuals show impaired homing of circulating T cells to the skin [19], undermining local tumor surveillance. Taken together, these changes—T-cell exhaustion, waning APC function, Treg/MDSC accumulation, and cytokine imbalances—create an immune landscape in older patients that can be tipped toward tumor tolerance and the evasion of immune surveillance.

2.2. Tumor Microenvironment in the Older Population

The TME in older patients with cSCC reflects intrinsic tumor factors and an aged host milieu. Chronic ultraviolet (UV) exposure, which is common in the older population, not only drives the high mutational burden of cSCC but also causes cumulative dermal damage and senescence in the surrounding stroma [20]. Senescent fibroblasts in aged skin acquire a pro-inflammatory, pro-tumor phenotype: they secrete growth factors (e.g., IL-6, IL-8, vascular endothelial growth factor) and matrix-degrading enzymes that promote cancer cell proliferation, angiogenesis, and invasion. Tumor cells can “educate” resident fibroblasts into cancer-associated fibroblasts resembling senescent cells, suggesting that an aged stromal environment may be especially permissive for tumor progression [20]. Moreover, TGF-β, often elevated in photoaged skin [21], can suppress effective antitumor immunity [16] and has been implicated in resistance to checkpoint inhibitors by excluding T-cell infiltration [22]. In older patients with cSCC and related squamous cancers, the TME is often enriched with immunosuppressive elements, such as Tregs. Azzimonti et al. reported that Treg infiltration was greater in cSCC than in normal skin, with particularly high levels observed in moderately to poorly differentiated (more invasive) lesions. They also showed that aggressive SCC subtypes exhibited a reduced CD8+/Treg ratio, underscoring the association between Treg predominance and tumor aggressiveness [23]. An aged TME may also show reduced T-cell trafficking; effector T lymphocytes in older individuals infiltrate the skin less efficiently, partly because of diminished endothelial adhesion molecule expression and altered chemokine signaling [19], a phenomenon likely relevant to cSCC.

Despite these challenges, some aspects of the aging TME may paradoxically favor responses to immunotherapy. Chronic antigenic stimulation in the older population can lead to clonal expansion of certain T cells, including tumor-specific clones [18], and cSCC tumors in older patients often harbor extremely high neoantigen loads because of UV-induced DNA damage [24]. A high tumor mutational burden is associated with improved survival, and in some studies, greater responsiveness to PD-1 blockade [25] suggests that the abundance of neoantigens may, at least in part, counterbalance age-related immune senescence. Additionally, although systemic Tregs increase with age, intratumoral Treg density is not necessarily higher in older patients. In melanoma, FOXP3⁺ Tregs were found to be less abundant in tumors from older individuals compared with those from younger ones, resulting in a more favorable effector (CD8⁺) to Treg ratio within the TME [26]. This may reduce local immunosuppression and improve the efficacy of checkpoint inhibitors in older tumors. Overall, the aged cSCC microenvironment is a combination of heightened tumor antigenicity and immunosuppressive host factors. Understanding this balance is the key to predicting how PD-1 inhibitor therapy should be administered to geriatric patients.

3. Standard Local Therapies and Their Limits

cSCC is typically managed with local therapies, such as surgical excision, which is often curative for most primary tumors, and radiotherapy as an adjunct or alternative when surgery is not feasible. However, these local treatments have important limitations in a subset of patients. Although >90% of patients with cSCC exhibit relatively indolent behavior, a minority progress to advanced disease, locally extensive or metastatic, that cannot be adequately controlled by surgery or radiotherapy [27]. High-risk tumors, such as large, deeply invasive lesions or those with perineural invasion, are associated with an increased risk of recurrence and metastasis [28,29]. Overall, approximately 5% of cSCC develop metastases [28,29]. In advanced cSCC, curative resection may be impossible or may be associated with unacceptable morbidity [30]. Moreover, not all patients can tolerate aggressive surgery, particularly older individuals or those with significant comorbidities [31,32]. Although radiotherapy can improve local control or serve as the primary treatment for inoperable cases, it is generally insufficient when the disease is widespread or metastatic. These limitations are particularly pronounced in older patients for whom comorbidities, frailty, or reduced tolerance to surgery and radiotherapy often further restrict curative options. In such situations, local interventions alone are inadequate, and systemic therapy is necessary for disease control [30,33].

4. Systemic Treatment Strategies for Advanced cSCC

Until recently, systemic options for advanced cSCC were limited and generally ineffective. Cisplatin-based chemotherapy, often combined with 5-fluorouracil or taxanes, and the epidermal growth factor receptor (EGFR) inhibitor cetuximab have historically been used off-label in cSCC, drawing on regimens for head and neck squamous cell carcinoma [34]. These approaches achieved only modest responses, with an overall response rate of approximately 20–30% and a median response duration of approximately 5 months, and were further constrained by short-lived responses and significant toxicity [35]. Nevertheless, EGFR inhibition remains an option for patients who are ineligible for immunotherapy, such as transplant recipients or those with uncontrolled autoimmune diseases. In addition, ongoing translational research is exploring molecularly targeted approaches based on frequent alterations in pathways, such as NOTCH, MAPK, and PI3K in cSCC [36,37], although these remain investigational. Although PD-1 inhibitors have become the standard first-line therapy, targeted therapies retain a niche role and may expand as precision oncology advances.

Therefore, the current European guidelines recommend that treatment decisions for advanced cSCC be made in a multidisciplinary setting, explicitly weighing toxicity risks along with patient age, frailty, and comorbidities [38]. More recently, ICIs, especially PD-1 inhibitors, have fundamentally changed this landscape. Given the high UV-induced mutational burden of cSCC and its association with impaired immune surveillance, PD-1 blockade is a biologically rational and clinically effective strategy [39]. ICIs have markedly improved outcomes, with more favorable tolerability than that of prior systemic therapies.

4.1. Evidence from Clinical Trials

PD-1 inhibitors are currently established as standard systemic therapies for advanced or unresectable cSCC. In pivotal trials, cemiplimab achieved an objective response rate (ORR) of 41.1–50% with durable responses and 3–4-year survival >70% in advanced cSCC (both locally advanced and metastatic disease) [33,40,41]. Pembrolizumab showed comparable efficacy, with ORRs of 35.2% (recurrent/metastatic) to 50% (locally advanced) and a median duration of response (DOR) not reached [42,43]. In the CARSKIN trial, pembrolizumab achieved an ORR of 42% in first-line unresectable disease, with a greater benefit in programmed death-ligand 1 (PD-L1)-positive tumors [42]. Pacmilimab, tested in a small cSCC cohort (n=14), showed an ORR of 36%, including one complete response; however, the DOR and survival outcomes were not evaluated (several ongoing responses >12 months) [44]. Both cemiplimab and pembrolizumab demonstrated manageable safety, with grade ≥3 treatment-related adverse events in 11–13.9% of patients. Table 1 summarizes the key trials.

4.2. Insights from Real-World Evidence

Real-world cohorts provide complementary insights into the feasibility of using PD-1 inhibitors in broader patient populations. Across Europe, cemiplimab cohorts have confirmed ORRs of 32–76.7% and 1-year overall survival (OS) of approximately 60%, although tolerance was reduced in very older subgroups [45,46,47,48]. The US series also demonstrated activity, with ORRs 26.7–42.3% and responses linked to tumor mutational burden and head/neck primaries [49,50]. In Latin America, nivolumab produced an ORR of 58.3%, with no complete response; however, its feasibility has been demonstrated [51]. In Australia, a large multicenter cohort (n=286; median age, 75.2 years) showed an ORR of 60% and a 1-year OS rate of 78%, including 31% immunocompromised patients; Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥2 was observed in 21% of the patients [52]. A separate single-center study (n=53; median age, 81.8 years) reported an ORR of 57% (complete response, 33%) with a 1-year OS rate of 63% and confirmed worse outcomes in patients with ECOG PS ≥2 [53]. Japanese data, although limited (n=14), showed an ORR of 57.1% and a 1-year OS rate of 73.1% [54]. Table 2 summarizes regional real-world outcomes.

Taken together, these findings indicate that chronological age or comorbidity does not consistently diminish ICI efficacy in cSCC; rather, poor PS (ECOG PS ≥2) is the most consistent predictor of inferior survival.

5. Geriatric Oncology Principles in Practice

Older patients with cSCC often present with unique challenges that necessitate a geriatric oncology approach. Chronological age alone is a poor surrogate of a patient’s true physiological reserve [55,56]. Many patients in their 70s or 80s are robust and can tolerate therapy well, whereas others are frail, have a multidimensional state of decreased functional reserve, and are at a higher risk of adverse outcomes. Standard PS scores (ECOG PS or Karnofsky) often miss these nuances, as comprehensive geriatric assessments reveal hidden vulnerabilities even in “fit” older adults [55,56]. For example, 69% of older patients with cancer with normal PS had at least one deficit, commonly polypharmacy (≥9 drugs in 43%) or multiple comorbidities (≥4 in 25%) [57]. These findings underscore that routine oncology evaluations may underestimate patient risk, and guidelines recommend geriatric screening for those aged ≥65 years starting systemic therapy. Assessing domains, such as function, comorbidities, cognition, nutrition, and social support, provides individualized care [55,56].

A critical implication of these hidden frailties is their impact on immunotherapy tolerance and safety. ICIs, such as anti-PD-1 antibodies, have become key systemic treatments for advanced cSCC, especially in older patients. Chronological age alone does not increase immune-related adverse events (irAEs) [58,59,60]; instead, frailty and comorbidity drive outcomes. For instance, mild toxicities, such as diarrhea, may precipitate dehydration or kidney injury in frail octogenarians, and steroids for irAEs may trigger delirium or infection [61,62]. In real-world analyses, irAE incidence was comparable to trial data, but patients with ECOG PS ≥2 had worse survival [53]. Similarly, frail patients with melanoma had higher hospitalization rates despite similar rates of grade ≥3 irAEs [63].

Polypharmacy further amplifies risks, as >40% of older adults take ≥9 drugs daily, increasing the likelihood of adverse drug events and drug–drug interactions that require careful consideration when initiating immunotherapy [57,61]. Multidisciplinary coordination among geriatricians, pharmacists, and caregivers is crucial because even low-grade toxicities may require early intervention in patients with frailty.

Importantly, advanced age should not prevent patients with cSCC from receiving immunotherapy. Pivotal PD-1 trials enrolled many older adults (median age, 70s) and demonstrated ORRs of approximately 40–50% [33,64]. Real-world cohorts confirmed similar outcomes: ORRs were approximately 50% in a French expanded-access program [46], approximately 60% in an Australian series [52], and 76.7% in a frail Italian cohort [48]. Responses were observed even in immunosuppressed patients, indicating that efficacy is preserved. The strongest predictor of survival is functional status; in France, the 1-year OS rate was 73% with ECOG PS 0–1 versus 36% with ECOG PS ≥2 [46]. Similarly, US data showed that ECOG PS ≥3, not age ≥75 years, predicted worse survival [65]. Thus, a fit 80-year-old may benefit as much as younger patients, whereas a frail counterpart may face a higher risk. The challenge is to identify the modifiable vulnerabilities and intervene accordingly.

Integrating geriatric principles, screening for vulnerabilities with tools, such as the Geriatric-8 (G8), optimizing comorbidities and medications, early irAE management, and aligning goals of care, maximizes benefits while minimizing harm [66,67,68]. Shared decision-making is essential for tailoring therapy to patient priorities and balancing cure with palliation.

By applying these practices, clinicians can safely extend the advances in immunotherapy to a growing population of older patients with cSCC. Octogenarians and nonagenarians can achieve excellent outcomes if appropriately selected [69]. This emphasis must remain on physiological rather than on chronological age [70]. Tailoring care in this manner will ensure that advances in immunotherapy translate into real-world survival and quality-of-life gains for this vulnerable group.

6. Regional Perspectives: East Asia and Japan

As summarized in Section 4.2, most real-world evidence to date has come from Europe, the United States, and Australia, where outcomes with PD-1 inhibitors closely mirror those observed in clinical trials. However, data from East Asia are limited. In Japan, early real-world experiences have recently been reported, demonstrating response rates and safety outcomes that are consistent with international trial data [54]. These findings indicate that Japanese patients with cSCC respond to immunotherapy similarly to their Western counterparts, with no unexpected safety concerns.

6.1. Optimizing Treatment Sequences

The advent of ICIs has shifted treatment paradigms across East Asia. Historically, cytotoxic chemotherapy and EGFR inhibitors, such as cetuximab, were occasionally used in unresectable cSCC, but their antitumor activity was limited, with only modest response rates reported in international studies [34,71]. Given their limited efficacy, these targeted agents have been largely supplanted by ICIs as first-line systemic therapy. Consequently, current practice in Japan and elsewhere favors PD-1 inhibitors as initial therapy for advanced cSCC [54]. Studies have explored how best to sequence or combine these modalities. The recent I-TACKLE study in Italy examined the effects of cetuximab after PD-1 inhibitor failure [72]. This approach achieved a cumulative ORR of 63% using cetuximab to overcome pembrolizumab resistance and elicited responses in 10 of 23 resistant patients (43%). However, this sequential strategy comes at the expense of increased toxicity. EGFR blockade causes skin toxicities; in a phase II cetuximab monotherapy trial, 78% of patients developed an acneiform rash, generally grade 1–2 [34]. Thus, although adding cetuximab may benefit a subset of ICI-refractory patients, clinicians should be mindful of the risk of rash and other EGFR-related adverse effects, which are often low grade and manageable in routine practice.

6.2. Tolerability and Unique Considerations in East Asian Populations

Overall, the available evidence indicates that East Asian patients tolerate immunotherapy, as well as Western patients. However, there are ethnic considerations. Certain irAEs may occur more frequently in Asian populations than in non-Asian populations. For example, interstitial lung disease and ICI-related pneumonitis have been reported relatively frequently in Japanese cohorts, which likely reflects a higher baseline risk of drug-induced interstitial lung disease in this population [73]. Similarly, immune-related hepatitis, typically presenting as elevations in liver enzyme levels, requires particular vigilance in East Asia, where chronic hepatitis B virus (HBV) infection remains highly prevalent and contributes to the risk background for irAEs; in Japan, attention is paid to HBV reactivation during ICI therapy [74,75].

In response to these risks, oncologists in Japan and neighboring countries carefully screen for latent infections and monitor hepatic function during ICI therapy. Importantly, these factors can be managed with proper precautions and do not preclude effective treatment. In practice, Japanese patients have tolerated ICIs well, with efficacy and safety outcomes comparable to those in Western trials and no new safety signals observed [54]. This finding is consistent with the broader oncology experience, as studies in Asian lung cancer populations have also demonstrated outcomes similar to those in Caucasian patients [73,76]. In summary, the regional experience, albeit early, suggests that ICIs are transforming advanced cSCC care in East Asia, just as they have elsewhere. Japan has led regional adoption, reporting response rates on par with global benchmarks. Across East Asia, ICIs are increasingly used for cSCC, and although published data remain limited, there is no evidence of their reduced efficacy. Ongoing research and postmarketing surveillance will refine treatment strategies, but the current findings are encouraging: Japanese and East Asian patients can achieve excellent results with immunotherapy, validating its role as the first-line standard of care across diverse populations. These regional experiences underscore not only the comparable efficacy of immunotherapy in East Asia but also the need for continued refinement of treatment strategies. This naturally leads to broader questions about how cSCC management can evolve in the future, particularly in terms of predictive biomarkers, treatment sequencing, and the integration of geriatric principles into standard care.

7. Future Directions and Unmet Needs

One major direction is the development of predictive biomarkers to guide immunotherapy selection, as no robust markers, such as tumor mutational burden, PD-L1 status, or CD8⁺ T-cell infiltration, have yet been established, despite the high immunogenicity of cSCC [77]. Its tumor mutation burden is among the highest among all cancers, and PD-L1 is frequently expressed [39,77]. Evidence suggests that PD-L1-positive tumors have high response rates to PD-1 inhibitors, underscoring the need to validate these biomarkers in prospective studies [42].

Another emerging strategy is neoadjuvant immunotherapy, which has achieved approximately 50% pathological complete response and 89% 1-year event-free survival in high-risk resectable cSCC, demonstrating remarkable efficacy and addressing the unmet needs in this setting [78].

Recent phase III evidence also supports adjuvant PD-1 blockade after surgery for high-risk cSCC, indicating that perioperative immunotherapy may further improve long-term outcomes [79].

Finally, integrating frailty tools and geriatric assessments into treatment planning is crucial for the predominantly older patients with cSCC [67]; instruments, such as the G8 index, can predict treatment tolerability, including postoperative complications, and Japan-based initiatives advocate incorporating such geriatric assessments in clinical trials to optimize therapy for older patients with cSCC. Multidisciplinary collaboration between geriatric medicine and oncology is essential for optimizing care in super-aged societies, such as Japan.

8. Conclusion

In the context of aging societies, particularly in East Asia, where older patients represent a growing majority of cSCC cases, optimizing management requires careful consideration of regional characteristics and age-specific vulnerabilities. ICIs have fundamentally expanded the therapeutic landscape for cSCC, offering durable tumor control and improved survival, even in older patients who comprise the majority of cases in super-aged societies. Although surgery and radiotherapy remain indispensable curative modalities for early-stage diseases, their integration with systemic immunotherapy is essential for advanced or unresectable tumors. To maximize the benefits of immunotherapy in older populations, the incorporation of geriatric oncology principles, particularly structured assessments of frailty, comorbidities, and polypharmacy, should be prioritized in clinical practice and research. In East Asia, Japan in particular, the accumulation of regional real-world evidence and consideration of unique healthcare and socioeconomic factors will be key to refining treatment strategies. Establishing multidisciplinary frameworks that link dermatology, oncology, and geriatric medicine is crucial for optimizing outcomes and adapting cSCC management to the realities of aging societies worldwide.