Citation
Miller DM. The evolving treatment landscape for CSCC. Arch Dermatol Res. 2025;317:502. doi:10.1007/s00403-025-03933-5.
Why this review matters
Surgery and radiotherapy remain foundational for localized cutaneous squamous cell carcinoma, but immune checkpoint inhibition has changed what is possible for patients with advanced disease and is now moving into earlier stages of care.
This transition creates opportunities for tumor downstaging, organ preservation, reduced surgical morbidity, localized immune treatment, and potentially even immunoprevention. It also requires dermatologists to engage more deeply with systemic therapy, multidisciplinary decision-making, and immune-related toxicity.
The CSCC treatment landscape is no longer organized around surgery versus systemic therapy. The emerging model is response-directed and multidisciplinary: use immunotherapy when it can improve resectability, preserve function, reduce treatment intensity, or address disease risk that local therapy alone cannot adequately manage.
Advanced disease established the foundation
Objective response rate
Durable tumor responses established PD-1 blockade as a transformative option for locally advanced and metastatic CSCC.
Objective response rate
KEYNOTE-629 provided additional evidence that PD-1 inhibition could produce meaningful activity with a manageable safety profile.
First CSCC-specific systemic approval
Cemiplimab became the first systemic therapy specifically approved for advanced CSCC.
Responses beyond chemotherapy
Checkpoint inhibition replaced transient, toxic chemotherapy responses with a realistic possibility of long-term control.
Neoadjuvant immunotherapy
The neoadjuvant strategy uses immune checkpoint inhibition before surgery to reduce viable tumor, improve resectability, and potentially lessen the morbidity of definitive local treatment.
Pathologic response
Fifteen of 20 patients responded pathologically, including an estimated 55% complete response rate.
Pathologic response
Neoadjuvant cemiplimab generated frequent deep responses and encouraging early disease-control outcomes.
Pathologic complete response
Some patients were able to avoid the originally planned surgery after major clinical response.
pCR or major downstaging
Response-adapted postoperative management allowed more conservative treatment for selected patients.
The value of preoperative immunotherapy is not limited to shrinking tumors. Pathologic response can become a decision tool—informing the extent of surgery, postoperative radiation, additional systemic therapy, and, in selected cases, whether surgery remains necessary.
Why treatment before surgery may matter
Preserved immune architecture
Treating while the tumor and draining lymphatic system remain intact may support broader antigen presentation and more effective immune priming.
Pathologic response as an early marker
The resection specimen provides a direct measure of treatment effect that can guide subsequent therapy.
Opportunity for de-escalation
Deep response may permit less extensive surgery, omission of postoperative radiation, or surveillance rather than automatic additional treatment.
Lessons from melanoma
Randomized melanoma trials suggest that perioperative treatment beginning before surgery can outperform adjuvant-only immunotherapy.
The adjuvant evidence gap
Adjuvant-only immunotherapy initially appeared to be a natural extension of success in advanced CSCC, but the optimal timing of treatment remains uncertain. The halted KEYNOTE-630 program underscored that activity in advanced disease does not automatically translate into benefit after definitive local therapy.
The central question is therefore not simply whether immunotherapy works in CSCC, but when tumor antigen exposure, disease burden, and immune context make treatment most effective.
Intralesional immunotherapy
Direct injection of checkpoint inhibition into a tumor offers a potential bridge between local procedural treatment and systemic immunotherapy. This approach is especially attractive for dermatologists because it could be delivered in-office while limiting systemic exposure.
Patients treated
Intralesional cemiplimab was administered weekly in a dose-escalation study.
Thirteen of 17 patients
Early tumor-control results supported further evaluation in localized CSCC.
Serious toxicity remained possible
Local administration did not eliminate the need for systemic immune-toxicity surveillance.
Phase III comparison
The trial compares intralesional cemiplimab with margin-controlled surgery for selected early-stage tumors.
Intralesional immunotherapy could move checkpoint inhibition into routine dermatologic practice, but “local” treatment should not be mistaken for risk-free treatment. Systems for recognizing and managing systemic immune effects remain essential.
From chemoprevention to immunoprevention
Patients with actinic neoplasia syndrome or repeated CSCCs remain difficult to manage. Existing preventive options—including nicotinamide, retinoids, and capecitabine—can be useful, but their efficacy, tolerability, or durability is often limited.
- Nicotinamide is accessible and generally well tolerated but may be less effective in some immunosuppressed populations.
- Retinoids can reduce new tumors but are limited by mucocutaneous toxicity, metabolic effects, and rebound after discontinuation.
- Capecitabine may reduce new CSCCs in selected high-risk patients but requires management of gastrointestinal and hand-foot toxicity.
- Observational signals suggest that anti–PD-1 therapy may reduce the incidence of new keratinocyte cancers.
- Prospective studies are needed to define dose, schedule, duration, safety, and the population in whom immunoprevention could justify systemic risk.
The expanding role of dermatologists
Identifying candidates
Dermatologists are often best positioned to recognize high-risk disease, field cancerization, recurrence patterns, and opportunities for organ-preserving treatment.
Delivering localized therapy
Intralesional treatment could integrate naturally with procedural dermatology and longitudinal skin-cancer care.
Interpreting response
Clinical examination, photography, pathology, and longitudinal surveillance are central to response-directed management.
Managing systemic risk
Checkpoint inhibitors can cause gastrointestinal, endocrine, hepatic, pulmonary, neurologic, and other immune toxicities that require rapid multidisciplinary care.
As immunotherapy moves closer to routine dermatology, the specialty will need new training, referral pathways, and co-management structures. Expanding therapeutic scope without expanding toxicity expertise would be unsafe.
A practical framework
- Use multidisciplinary review for high-risk, resectable, function-threatening, or anatomically complex disease.
- Define the therapeutic intent before treatment: cure, downstaging, organ preservation, local control, or prevention.
- Assess response early and use it to guide the intensity of subsequent surgery, radiation, or systemic therapy.
- Do not assume that intralesional administration eliminates systemic immune risk.
- Build explicit pathways for urgent evaluation of possible immune-related adverse events.
- Prioritize clinical trials when the proposed use extends beyond established evidence.
Immunotherapy is broadening the range of achievable outcomes in CSCC—from durable control of advanced disease to less morbid surgery, local injection, and perhaps future prevention. The next phase of progress will depend on matching the right strategy to the right patient and coordinating care across dermatology, surgery, radiation oncology, and medical oncology.
Author
David M. Miller.