Immunotherapy in Merkel Cell Carcinoma of the Skin: A 2025 Comprehensive Review

1. Introduction

Merkel cell carcinoma (MCC) is a rare but highly aggressive neuroendocrine skin cancer, often associated with Merkel cell polyomavirus (MCPyV) or ultraviolet-induced mutations [1]. Despite its low incidence, MCC carries a disproportionately high mortality rate, with five-year survival estimates ranging from 30%–60% depending on stage and treatment modality.

Historically, treatment options were limited to surgery and radiation, with chemotherapy offering modest and short-lived benefits [2]. However, the emergence of immune checkpoint inhibitors (ICIs) has dramatically reshaped the therapeutic landscape.

Following the American Food and Drug Administration (FDA) approval in 2017, ICIs are now employed in both routine clinical practice and ongoing clinical trials [3,4]. The first ICI approved for MCC was avelumab (Bavencio), which received accelerated approval in March 2017. This milestone marked the first FDA-sanctioned treatment specifically for metastatic MCC [5,6].

Programmed Death-Ligand 1 (PD-L1) is a protein that plays a key role in regulating immune responses. PD-L1 binds to its receptor PD-1 on T cells, effectively putting the brakes on the immune system and allowing some cancer cells to evade detection [7]. Immunotherapy, particularly agents targeting the PD-1/PD-L1 axis, has demonstrated durable responses in advanced MCC, prompting investigations into its role across the disease continuum—from neoadjuvant and adjuvant settings to primary and salvage therapy [8]. Yet, despite promising clinical outcomes, published data remain limited, and questions persist regarding optimal timing, integration with other treatment modalitiies, patient selection and mechanisms of resistance [9].

This comprehensive review aims to synthesize current evidence scattered across the literature on immunotherapy in MCC, with a focus on key clinical trials, treatment strategies, and future directions. This work is unique for several reasons: (1) We followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) methodology, which, to our knowledge, has not previously been applied to MCC in the published literature. (2) As clinicians with direct experience managing this rare cancer, we provide expert recommendations to improve current treatment patterns. Our team compiled a robust database of 949 patients, including 303 who presented to our respective cancer centers in Canada, France, and Australia between March 1982 and February 2015 [10]. The remaining patients were drawn from individual patient data extracted from published case reports and series. (3) The most updated literature in 2025 and all major landmark studies are summarized to provide the best comprehensive bedside information for healthcare providers on MCC.

2. Methods

A comprehensive search was conducted across four databases: Scopus, ScienceDirect, PubMed, and MEDLINE (an acronym for Medical Literature Analysis and Retrieval System Online). The keywords “Merkel cell carcinoma” AND “immunotherapy” were used to identify peer-reviewed articles published between January 2000 and March 2024. Inclusion criteria encompassed clinical trials, observational studies, and meta-analyses evaluating immunotherapy in MCC. Exclusion criteria included non-English publications, case reports and studies lacking immunotherapy-specific outcomes. The data were extracted and evaluated by the first two coauthors (P.T. and O.A). Any disagreements were discussed with the intervention of a third researcher. The PRISMA methodology was employed. Data extraction focused on study design, patient population, treatment regimen, response rates, progression-free survival (PFS), overall survival (OS), and reported adverse events. Studies were categorized by treatment setting: neoadjuvant, adjuvant, and primary therapy.

3. Results

The search and study selection process is summarized in the PRISMA flow diagram (Figure 1). A total of 350 records were identified from the databases: Scopus (N=120), PubMed, MEDLINE (N=140), and ScienceDirect (N=90). After removing 70 duplicate entries, 280 records remained for screening. Following a title and abstract review, 180 records were excluded based on irrelevance to the study objectives or failure to meet inclusion criteria. Then the full texts of 100 articles were assessed for eligibility. Of these, 80 were excluded due to reasons such as lacking clinical data, insufficient information on immunotherapy intervention, or inappropriate study design. Finally, twenty articles satisfied all requirements and are summarized in this review.

3.1. Neoadjuvant Immunotherapy

The rationale for short-course preoperative immuno-oncology (IO) therapy is that it may induce significant tumor regression, allowing for less extensive surgical resection and improving long-term outcomes. Moreover, neoadjuvant therapy can prime the immune system by exposing it to intact tumor antigens, thereby enhancing systemic anti-tumor immunity. It also serves as an early in vivo test of therapeutic sensitivity for individual patients. If the pathological response is suboptimal, alternative adjuvant treatments can be selected postoperatively.

The CheckMate 358 trial represents a landmark study in the neoadjuvant setting [11]. This phase I/II trial evaluated nivolumab, a PD-1 inhibitor, in patients with resectable MCC. Among 33 radiologically evaluable patients, 54.5% achieved tumor reductions exceeding 30%, with pathologic complete responses (pCR) observed in nearly half. In particular, neoadjuvant nivolumab was well tolerated, with no delays in planned surgery and minimal grade 3–4 adverse events.

3.2. Adjuvant Immunotherapy

The ADMEC-O phase II trial investigated adjuvant nivolumab versus observation in patients with completely resected MCC [12]. Conducted across 20 academic centers in Germany and the Netherlands, the study enrolled 179 patients, randomized in a 2:1 ratio to receive nivolumab or observation. Nivolumab or OPDIVO® (480 mg) was administered intravenously every 4 weeks for up to 1 year (ie, a maximum of 13 doses). At 12 months, disease-free survival (DFS) was 85% in the nivolumab group versus 77% in the control group. Although the difference did not reach statistical significance, the trend favored immunotherapy. However, 42% of patients receiving nivolumab experienced grade 3–4 adverse events, including rash and endocrine dysfunction. These findings emphasize the need for careful patient selection and monitoring, especially in the adjuvant setting where patients may be asymptomatic.

The ADAM phase III trial evaluates adjuvant avelumab, a PD-L1 inhibitor, in node-positive MCC patients following surgery and radiation [13,14]. This study, also known as the MCC trial, is a multicenter, randomized, double-blinded, placebo-controlled trial involving patients with nodal metastases from MCC. Participants receive avelumab 10mg/kg intravenously over 1 hour every 15 days during Induction Phase 1 (days 0–120), every 30 days during Induction Phase 2 (days 121–240), and every 120 days during the Maintenance Phase, for up to a total of 720 days (approximately 2 years), provided there is no disease progression or unacceptable toxicity [15]. The trial has completed accrual. Preliminary data suggest improved DFS, with common side effects including nausea, fatigue, and pruritus. The trial aims to clarify whether adjuvant IO can reduce recurrence risk in high-risk patients.

The Surgically Treated Adjuvant Merkel cell carcinoma with Pembrolizumab (STAMP) trial of the Dana-Farber Cancer Institute, another phase III study, has also completed accrual [16]. It assesses the use of pembrolizumab in patients with stage I–III MCC after complete resection (Table 1). It is one of the largest and most comprehensive efforts to define the role of adjuvant immunotherapy in early-stage MCC, potentially expanding its role beyond advanced MCC. The STAMP trial (NCT03712605) is led by U.S. institutions and coordinated by the ECOG-ACRIN Cancer Research Group [17], it includes a broad network of participating centers across the United States, but does not list international sites. While results are pending, preliminary data suggest favorable tolerability and immune activation.

The I-MAT (NCT04291885), a randomised, placebo-controlled, phase II trial of adjuvant Avelumab in patients with stage I-III Merkel cell carcinoma aiming to explore the efficacy of avelumab as adjuvant immunotherapy to prevent recurrence (Table 2) [18,19]. Its comparison with STAMP trial is listed in Table 3 for clarity.

3.3. Primary Therapy and Salvage Use

As some patients with MCC are inoperable due to their performance status or disease stage is too advanced to be resected, use of immunotherapy has developed over the years and gained adequate experience to conduct large clinical trials [20,21].

The KEYNOTE-017 trial evaluated pembrolizumab as first-line therapy in advanced MCC [22]. Among treatment-naïve patients, the overall response rate (ORR) was 56%, with complete responses in 24%. At three years, progression-free survival (PFS) was approximately 40%, and overall survival (OS) exceeded 60%. These outcomes compare favorably to historical chemotherapy data, which typically yield short-lived responses and high toxicity.

The JAVELIN trial assessed avelumab in patients with metastatic MCC who had progressed after chemotherapy [23,24]. The ORR was 33%, with durable responses in a subset of patients. Avelumab was well tolerated, with manageable immune-related adverse events. Importantly, responses were observed in both virus-positive and virus-negative tumors, suggesting broad applicability. The latest update was in 2024 [25].

Both pembrolizumab and avelumab have demonstrated efficacy as salvage therapies in patients who relapse after initial treatment [26]. Retreatment or switching agents may be considered, although data are limited. Standard strategies nowadays include chemotherapy, radiotherapy, surgery and combination immunotherapy. Emerging strategies are intralesional STING agonists [], and therapeutic vaccines [], to overcome resistance. Extracted summary is shown in Table 4.*

3.4. Mechanisms of Resistance

encouraging outcomes, immunotherapy resistance remains a significant challenge. Treatment resistance was defined by the Society of Immunotherapy for Cancer consensus recommendations [46]:

* Primary resistance (upfront progressive or stable disease with subsequent progression, having received at least 6 weeks and up to 6 months of anti-PD-(L)1 therapy).

* Secondary resistance - upfront partial or complete response with subsequent progressive disease, or stable disease for > 6 months prior to progression disease, after at least 6 months of anti-PD-(L)1 therapy, with progression occurring ≤12 weeks of anti-PD-(L)1 therapy cessation.

* Late progression - if patient had upfront complete/partial response or stable disease for > 6 months prior to progression, with progression occurring > 12 weeks following anti-PD-(L)1 therapy discontinuation.

Several mechanisms have been proposed for drug resistance:

(1) Intra-tumoral STING activation: While STING agonists can enhance immune responses, chronic activation may lead to immune exhaustion or paradoxical suppression [*]. The STING protein was found to be absent in MCC cells themselves, but present in the surrounding immune and stromal cells within the tumor microenvironment [47]. This suggests that STING activators may exert their effects indirectly in MCC, by signaling through these non-tumor cells, rather than acting directly on cancer cells [*]. This observation also suggests that resistance may not be due to chronic activation within cancer cells, but rather to a direct lack of STING expression in the target cells, or that its effect is dose-dependent, as high doses can lead to reduced efficacy or even cause “adverse effects.” [48].

(2) Tumor-associated macrophages (TAMs) can create an immunosuppressive microenvironment, inhibiting T-cell infiltration and function [49], as noted by Professor Ann Silk, a leading expert in Merkel cell carcinoma (MCC).

(3) Loss of major histocompatibility complex (MHC) class I expression: Downregulation of antigen presentation impairs recognition by cytotoxic T cells [50,51].

(4) T-cell exhaustion: Chronic antigen exposure may lead to dysfunctional T cells, characterized by upregulation of inhibitory receptors (e.g., TIM-3, LAG-3) [52,53].

(5) Immunosuppressive cytokines: Elevated levels of IL-10 and TGF-β may dampen anti-tumor immunity [54,55].

Understanding these pathways is critical for developing next-generation therapies, including combination checkpoint blockade, adoptive T-cell transfer [39 adjust#later]*, and personalized vaccines [56,57].

3.5. What Measures Will Have the Greatest Impact on Improving Outcomes in MCC?

Merkel cell carcinoma (MCC) shares clinical and biological characteristics with other aggressive skin cancers, notably melanoma. Immunotherapies such as nivolumab and pembrolizumab have demonstrated effectiveness across multiple stages of MCC presentation, leading to improved outcomes in some patients. Despite these advances, optimizing long-term prognosis still requires a multifaceted strategy.

Immunotherapy has significantly transformed the care of patients with MCC [58]. To date, our expert team proposes several actionable recommendations to improve MCC outcomes. First, increasing awareness among both healthcare professionals and the public is essential. MCC’s rarity and aggressive nature often delay recognition; timely education campaigns can promote earlier detection and intervention. Second, minimizing delays in diagnosis and ensuring swift referral to specialists is critical for initiating appropriate treatment before disease progression.

Third, stratifying patients into good- and poor-risk categories allows for personalized treatment planning based on tumor biology and clinical aggressiveness. Additionally, clinicians must carefully evaluate patients’ comorbid conditions to minimize both treatment-related toxicities and financial burdens—a concept now recognized as “financial toxicity.”

Regular follow-up is indispensable to monitor treatment response and detect recurrence. Emerging technologies such as circulating tumor DNA (ctDNA) assays, MCC polyomavirus viral titers, and advanced imaging modalities offer promising tools for early identification of disease relapse.

Cost-effectiveness must also guide the selection of diagnostic tests used for staging, surveillance, and re-staging at recurrence. Rational test utilization balances clinical benefit with resource stewardship. Finally, enhancing patients’ quality of life during and after treatment is vital. This includes minimizing adverse effects, supporting functional outcomes, and providing counseling that addresses psychological, sexual, and social well-being, as in the subsection below.

Taken together, this comprehensive approach aligns with a patient-centered paradigm and holds the greatest promise for improving both survival and quality of life in those affected by MCC.

3.6. Future Direction in Research in MCC: Combination Treatments, Biomarkers, Liquid Biopsy

The future of MCC treatment should involve multimodal integration, with immunotherapy combined with other modalities to improve outcomes and to minimize toxicity. Here’s how the landscape is evolving:

3.6.1. Adoptive T- Cell Transfer

Adoptive T-cell transfer (ATT) represents a promising approach, particularly in cases of MCC associated with the Merkel polyomavirus (MPV). For example, a single-patient clinical trial demonstrated that combining HLA-I-enhancing agents with MHC-specific T-cell therapy resulted in tumor regression and delayed the onset of distant metastases [59]. However, challenges remain, such as low MHC class I expression on tumor cells, which can limit the efficacy of the transferred T cells [60]. Future trials aim to address these challenges to increase the effectiveness of this approach [61].

3.6.2. Therapeutic Vaccines:

Therapeutic vaccines aim to stimulate a strong and specific immune response against cancer cells. They are a promising approach, especially in the context of resistance to current IO [62]. Various types of vaccines are being explored for MCC [63].

• Peptide-based vaccines: These vaccines consist of short peptide sequences of tumor antigens and require strong adjuvants to enhance the immune response. They are taken up by dendritic cells, which present them to T cells.
• mRNA vaccines: These vaccines use synthetic mRNA at the desired antigen concentration and are typically in a lipid-based compound. They have a good safety profile and the ability to rapidly stimulate the immune system.
• Vaccines based on oncolytic viruses: These vaccines aim to directly infect and destroy cancer cells, leading to the release of tumor antigens and stimulating an immune response. Examples include modified herpes simplex virus (RP1) [64,65] and oncolytic adenovirus (MEM-288) [66].
• Plasmid/viral vector vaccines: These use a virus to deliver genetic material that elicits an antigen, leading to an immune response. They can improve targeting of treatments to tumor sites and avoid excessive immune activation.
• Exosome-based vaccines: These use extracellular vesicles carrying membrane proteins to increase the immune response and can stimulate T cells similarly to dendritic cells.

Many of these vaccines are being combined with ICIs in ongoing studies to enhance immune responses and counteract resistance. However, enhancing immune responses through combination therapy may increase the risk of serious adverse events, such as those seen with nivolumab and ipilimumab (such as immune hypophysitis, thyroiditis, colitis, and hepatitis). Cytokine release syndrome is also a possibility [67,68]. However, directing the immune response specifically to cancer cells via vaccination may reduce some of the toxicities of ICIs.

3.6.3. Combining Different Treatment Modalities

Radiotherapy has a synergistic effect as it may increase tumor antigen presentation, making cancer cells more recognizable to the immune system [69]. In addition, shrinkage of the tumor will allow systemic therapeutic agents to reach cancer cells. By using different modalities can also decrease side effects if individual component of the combined therapy can be reduced in intensity, in terms of drug/radiotherapy dose or radiotherapy treatment volume. Careful design of clinical trials is needed as toxicities could increase with combined treatment. Current efforts such as the NCT03304639 study which is testing pembrolizumab with stereotactic body radiation therapy (SBRT) to improve PFS [70].

Adjuvant radiation may consolidate local control while immunotherapy targets systemic disease. Research should also focus on selecting the proper patients for postoperative radiotherapy with careful considerations on dose and volume.

Regarding chemo-immunotherapy combinations, many experts express concern about the immunosuppressive effects of chemotherapy and the diminished responses to immuno-oncology agents following prior chemotherapy. However, chemotherapy can reduce tumor burden and may act synergistically with immunotherapy by enhancing cytotoxic effects. Ongoing trials include the MERCURY (NCT05594290) evaluating retifanlimab with cisplatin and etoposide before surgery [71].

Lutetium-177 dotatate (a radiolabeled peptide) is tested in combination with avelumab or pembrolizumab in trials such as GoTHAM and iPRRT [72,73]. The combined treatment may confer targeted cytotoxicity while activating immune responses.

3.6.2. Biomarkers

Viral titers and ctDNA are used to monitor recurrence and guide treatment intensity in some well-off countries, such as the United States [74]. Recent data suggest that baseline levels of ctDNA may serve as early predictors of immunotherapy response, while longitudinal monitoring enables real-time assessment of minimal residual disease and recurrence. In a recent study, ctDNA positivity preceded radiographic relapse by several weeks, supporting its role as a dynamic biomarker in MCC surveillance [75].

PD-L1 status and MCPyV may help predict response to checkpoint inhibitors; however, access remains limited—even in Canada, where a significant proportion of the national budget is allocated to health care. There are long waiting lists for new consultations with medical oncologists, and subsequent biomarker testing on tissue specimens often involves turnaround times of several weeks. Although reflex ordering has been discussed, it has yet to be implemented in many smaller or rural hospitals across Canada.

3.6.4. Improving Quality of Life During and After Treatment

The following reflects expert opinions on minimizing complications and improving quality of life for patients with MCC. Infusion reactions to immunotherapy or chemotherapy are relatively common, and pre-medication protocols could be optimized through further research.

Rehabilitation is crucial to address both physical and psychosexual impacts of aggressive treatments like surgery and radiation. Maxillofacial prostheses (e.g., nose, ear) may be used following facial resection to restore aesthetic form and function, significantly boosting patient confidence. Lymphedema can be prevented through lymphovenous anastomosis and managed with physiotherapy, including exercise with or without compression garments. Physiotherapy also plays a critical role in addressing facial nerve damage and improving facial symmetry and expression.

Rehabilitation extends to psychological well-being, addressing body image concerns, anxiety, and relationship distress through psychosexual counseling and behavioral therapies [76,77]. Pelvic radiotherapy frequently results in long-term sexual dysfunction. Women may experience vaginal dryness, pain, and stenosis, while men may develop erectile dysfunction or reduced libido. Pelvic floor physiotherapy can be transformative for painful intercourse and overall pelvic health. Other effective rehabilitative strategies for female patients include vaginal lubricants, estrogen creams, and vaginal dilators to prevent vaginal obliteration or stenosis. Oncologists should provide these dilators and reinforce their use during follow-up visits. Successful implementation requires a multidisciplinary approach involving nurses and social workers as well.

For men, treatments for erectile issues are available. To improve post-treatment health, various modern rehabilitations are available. For example, erectile impotence can be treated by oral phosphodiesterase type-5 inhibitors as first-line treatment [78] or , Eroxon gel [79]. The latter is available over the counter and contains ethanol, propylene glycol and glycerine/glycerol. It works within 10 minutes, with few side effects apart from local skin reactions [80,81]. Other treatments are lifestyle interventions, psychological counseling and Kegel exercises. More invasive treatments include self-injections and penile implants (a surgical procedure available in most large Canadian cities).

Last but not the least, since patients with MCC often experience recurrence and poor outcomes, effective communication skills among healthcare workers are essential [82,83]. Ongoing medical and nursing education remains critically important [84,85]. Caring for cancer patients is both an art and a science.

In summary, a proactive multidisciplinary approach and open communication among health care team members and the patients are essential for optimizing patients’ quality of life following treatment. The examples presented above relate to situations in the Middle East, the United States, and Canada—regions in which members of this research team received training. It is our hope that these practices can be applied globally, with broad generalizability.

4. Conclusions

Immunotherapy has transformed Merkel cell carcinoma (MCC) management. This comprehensive review summarizes literature from four databases. Immunotherapy is administered either before (CheckMate 358) or after surgery (ADMEC-O, ADAM, STAMP), or solely in advanced disease (KEYNOTE-017 and JAVELIN trials).

The findings in this comprehensive review highlight the need for further clinical research to strengthen the evidence base and guide future therapeutic approaches. Hence, recommendations for improving care of MCC patients and future directions for research have been discussed.