# The tumor microenvironment of cutaneous squamous cell carcinoma in high-risk patient groups: A scoping review

## TL;DR

This review explores how the tumor environment in a skin cancer called cSCC differs in high-risk groups, aiming to find better treatments.

## Contribution

The study systematically compares tumor microenvironment features in two high-risk cSCC groups and identifies potential therapeutic targets.

## Key findings

- High-risk cSCC groups show a permissive tumor microenvironment with immune dysfunction and enhanced TGFβ signaling.
- Organ transplant recipients' cSCC is marked by immune exhaustion, while recessive dystrophic epidermolysis bullosa cSCC is driven by chronic tissue damage and matrix remodeling.
- Understanding these differences could lead to novel targeted therapies for improved outcomes in high-risk patients.

## Abstract

Cutaneous squamous cell carcinoma (cSCC) is a prevalent skin cancer in the general population that poses so far unresolved challenges in high-risk groups such as organ transplant recipients and individuals with recessive dystrophic epidermolysis bullosa. Although most cases of cSCC respond well to standard treatments, these 2 groups often face more aggressive disease, characterized by higher rates of metastasis and cancer-specific mortality. The tumor microenvironment plays a pivotal role in cSCC progression, influencing tumor growth, immune evasion, and therapy response. Therefore, this scoping review aims to systematically investigate how the tumor microenvironment in these high-risk cSCC differs from that of sporadic cSCC, highlight shared tumorigenic mechanisms, and identify knowledge gaps for future research. Specifically, we review immune cell infiltration, epithelial–mesenchymal transition, extracellular matrix remodeling, and related biomarkers, while also exploring potential therapeutic targets. It is surmised that both organ transplant recipients cSCC and recessive dystrophic epidermolysis bullosa cSCC may exhibit a permissive tumor microenvironment, potentially characterized by immune dysfunction and enhanced TGFβ signaling, contributing to tumor aggressiveness. Notably, organ transplant recipients cSCC primarily demonstrates immune exhaustion, whereas recessive dystrophic epidermolysis bullosa cSCC is driven by chronic tissue damage with concomitant extracellular matrix remodeling. A better understanding of tumor microenvironment features in these high-risk cSCC may help develop novel targeted therapies to improve patient outcomes.