# Tumor Infiltrating Lymphocytes in Cutaneous Squamous Cell Carcinoma—A Systematic Review

## TL;DR

This review explores how immune cells in skin cancer affect tumor growth and treatment outcomes, highlighting potential targets for better immunotherapies.

## Contribution

The paper systematically characterizes the TIL landscape in cSCC, identifying immune markers linked to prognosis and treatment response.

## Key findings

- CD8+ T-cells correlate with smaller tumors and better survival in cSCC.
- FOXP3+ cells and TGF-β2 signaling promote immune evasion in cSCC.
- Immunosuppressed patients show reduced CD8+ T-cell density and clonality.

## Abstract

Squamous cell carcinoma is a common skin cancer in which the body’s immune system plays an important role in controlling tumor growth. This cancer contains large numbers of immune cells called tumor-infiltrating lymphocytes. Theoretically, these immune cells are supposed to eliminate cancer, but they do not always work effectively. In this review, we examined decades of research to understand which immune cells help restrain cancer and which allow the cancer to progress. Killer T-cells, a type of tumor-infiltrating lymphocyte, can limit tumor growth when they are active and able to reach tumor cells. Regulatory and suppressive T-cells, along with tumor-associated signals, can block this response. Importantly, immune “brakes” targeted by modern immunotherapies often mark active immune responses rather than immune failure. These findings help clarify why immunotherapy works in some patients but not others and highlight new immune targets. This knowledge supports improved diagnostic interpretation and guides future research toward more precise, personalized immune-based treatments in squamous cell carcinoma.

Cutaneous squamous cell carcinoma (cSCC) is an immunogenic malignancy with variable immune infiltration and inconsistent responses to checkpoint blockade. Tumor-infiltrating lymphocytes (TILs) influence tumor progression and therapeutic outcome, yet their phenotypic and functional diversity across disease contexts remains incompletely understood. This review systematically characterizes the TIL landscape in human cSCC. Following PRISMA 2020 guidelines, PubMed and Embase were searched up to May 2025 and restricted to studies evaluating tumor-infiltrating lymphocytes in human cSCC, using the modified Newcatle–Ottawa score to assess risk of bias. Data were synthesized qualitatively given methodological heterogeneity. 48 studies met inclusion criteria. cSCCs exhibited dense CD3+ infiltrates composed of cytotoxic (CD8+GzmB+, Ki-67+, CD69+) and regulatory (FOXP3+, CCR4+) subsets. Higher CD8+ activity correlated with smaller tumors and longer disease-free survival, whereas FOXP3+ enrichment and TGF-β2 signaling promoted immune evasion. Immunosuppressed patients demonstrated diminished CD8+ density and clonality. Immune modulation with PD-1/PD-L1 blockade, imiquimod, HPV vaccination, or OX40 stimulation enhanced effector function. The cSCC immune microenvironment reflects a balance between cytotoxic and suppressive factors. Harmonizing multimodal immune profiling and integrating spatial context with systemic immune status may advance both prognostic stratification and therapeutic design.