# Immune Checkpoint Blockade Therapy for Advanced Cutaneous Squamous Cell Carcinoma in Immunosuppressed Patients, Transplant Recipients, and Individuals with Hereditary Syndromes: A Narrative Review

## TL;DR

This review explores how immune therapy can treat advanced skin cancer in patients with weakened immune systems or genetic conditions.

## Contribution

The paper compiles current evidence and challenges in using immune checkpoint inhibitors for high-risk skin cancer patients excluded from major trials.

## Key findings

- Immune checkpoint inhibitors like cemiplimab and pembrolizumab show durable responses in advanced cSCC due to high tumor mutational burden.
- High-risk groups such as transplant recipients and those with hereditary syndromes are often excluded from clinical trials, limiting treatment guidance.
- The review highlights gaps in evidence and emphasizes the need for tailored treatment strategies in vulnerable patient populations.

## Abstract

Cutaneous squamous cell carcinoma is one of the most common types of skin cancer and is usually treated successfully with surgery. However, in some patients, the disease spreads or becomes too advanced for surgery, leading to serious health risks and limited treatment options. In recent years, new drugs that help the immune system recognize and attack cancer cells have shown promising and long-lasting results. Unfortunately, people with weakened immune systems, chronic skin damage, or rare genetic conditions are often excluded from major clinical trials, leaving doctors uncertain about how best to treat them. This review aims to gather and explain what is currently known about treating advanced squamous cell carcinoma in these high-risk groups. The findings may help researchers and clinicians better understand how the immune system and tumor biology influence treatment response, and guide future studies to improve care for these vulnerable patients.

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer, with incidence steadily increasing due to cumulative ultraviolet (UV) exposure, impaired immune surveillance, and chronic tissue damage. While most cases are effectively managed with surgical excision, a subset progress to locally advanced or metastatic disease, associated with high recurrence rates, limited curative options, and poor prognosis. The introduction of immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis has significantly altered the management of advanced cSCC. Cemiplimab and pembrolizumab are now established systemic therapies, producing durable responses in a proportion of patients. These outcomes reflect the typically high tumor mutational burden and immunogenic microenvironment of cSCC. However, therapeutic decision-making remains particularly complex in several high-risk populations, including solid organ transplant recipients at risk of allograft rejection, patients with chronic dermatologic disorders or non-healing wounds that predispose to carcinogenesis, and individuals with rare hereditary syndromes such as recessive dystrophic epidermolysis bullosa. These so-called challenging populations are frequently excluded from pivotal trials, resulting in limited evidence regarding efficacy, safety, and optimal treatment strategies. This review summarizes current evidence on the management of advanced cSCC in high-risk and underserved patient groups, integrating trial data, real-world evidence, and contemporary guidelines. It also highlights key gaps in knowledge and outlines future directions, with particular focus on the interplay between host immune status, tumor biology, and therapeutic response.