TDO2 + Cancer-associated fibroblasts mediate cutaneous squamous cell carcinoma immune escape via impeding infiltration of CD8 + T cells

Sep 23, 2026

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Cutaneous squamous cell carcinoma (cSCC) is a common but incompletely understood cancer. Single-cell RNA sequencing identified marked upregulation of tryptophan 2,3-dioxygenase (TDO2) in cancer-associated fibroblasts (CAFs). TDO2 is confirmed as highly expressed in cSCC CAFs, with high levels linked to poorer tumor differentiation and reduced CD8+ T-cell infiltration. TDO2 inhibitors shrink tumors in mice, increase CD8+ T-cell infiltration, and modulate immune activity via downregulation of PI3K-Akt signaling. Overall, TDO2+ CAFs drive immune evasion and inhibiting TDO2 enhances antitumor immunity.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages13

Reading Time33 min

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Abstract

Introduction

Cutaneous squamous cell carcinoma background

Tumor microenvironment and CAF functions

TDO2 biology and immune escape relevance

Study approach and key findings

Cancer Immunology, Immunotherapy (2025) 74:67 [https://doi.org/10.1007/s00262-024-03921-0](https://doi.org/10.1007/s00262-024-03921-0) TDO2 + cancer‑associated fibroblasts mediate cutaneous squamous cell carcinoma immune escape via impeding infiltration of CD8 + T cells Fangqi Lu1 · Guorong Yan1 · Zijun Zhao1 · Zhe Zheng1 · Yuhao Wu1 · Long Wen1 · Yeqaing Liu2 · Qingyu Zeng1 · Guolong Zhang1 Received: 16 July 2024 / Accepted: 9 December 2024 / Published online: 3 January 2025 © The Author(s) 2024 Abstract Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer, originating from the malignant proliferation of squamous epithelial cells. However, its pathogenesis remains unclear. To further explore the mechanisms underlying cSCC, we analyzed the data from one single-cell RNA sequencing study and discovered a significant upregulation of tryptophan 2,3-dioxygenase (TDO2) in the cancer-associated fibroblasts (CAFs) . Nonetheless, the specific expression and potential biological significance ofTDO2 in cSCC have not yet been reported. In this study, we confirmed that TDO2 is highly expressed in CAFs of cSCC. Clinical correlation analysis indicated that high TDO2 expression was significantly associated with poor tumor differentiation. Furthermore, increased TDO2 expression in cSCC correlated with reduced CD8 + T cell infiltration, suggesting its role in modulating immune responses. TDO2 inhibitors significantly reduced the size and number of tumors in mice and effectively increased CD8 + T cell infiltration. RNA sequencing analysis revealed that TDO2 inhibitors modulate immune cell activity and downregulate the PI3K-Akt signaling pathway. In summary, our study demonstrates that TDO2 + CAFs induce immune evasion by inhibiting CD8 + T cell infiltration in cSCC. Inhibiting TDO2 could enhance antitumor immune responses, providing a promising strategy to improve treatment outcomes in cSCC. Keywords Cutaneous squamous cell carcinoma · Tryptophan 2,3-dioxygenase · Cancer-associated fibroblasts · Immune escape Introduction Cutaneous squamous cell carcinoma (cSCC) ranks as the second most prevalent type of non-melanoma skin cancer (NMSC), constituting about 20% of all NMSC cases [1] . Fangqi Lu and Guorong Yan have contributed equally to this work and shared the first authorship. * Qingyu Zeng [zengqingyu2011@tongji.edu.cn](zengqingyu2011@tongji.edu.cn) * Guolong Zhang [glzhangtj@tongji.edu.cn](glzhangtj@tongji.edu.cn) 1 Institute of Photomedicine, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai 200443, China 2 Department of Pathology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai 200443, China There has been a remarkable increase in the burden of SCC [2] . The disease predominantly affects the elderly, with a lifetime incidence rate ranging from 6 %to 11%[3], and the annual disease-specific mortality is estimated to be 1.5% to 2%[4] . Factors contributing to the increased incidence of cSCC include aging populations and enhanced skin cancer screening protocols [5] . Primary risk factors for cSCC include prolonged exposure to ultraviolet radiation, older age, male gender, and HPV infection [6]. Notably, high-risk cSCC patients experience a metastasis rate of up to 37% [7], with a median survival of less than two years for those with distant metastases [8], underscoring the critical need for early detection and intervention. The development and progression of cSCC are driven by intricate interactions within the tumor microenvironment (TME), which comprises a diverse array of tumor and nontumor cells, including immune cells, cancer-associated fibroblasts (CAFs), endothelial cells, and adipocytes [9] . These cells collaborate to promote tumor growth, dissemination, and treatment resistance through the secretion of cytokines, chemokines, extracellular matrix (ECM) components, and signaling molecules [10] . Mutations in keratinocyt

FAQs

What role does TDO2 play in cSCC-associated cancer-associated fibroblasts (CAFs)?

TDO2 is significantly upregulated in CAFs in cSCC. The study confirms TDO2 is highly expressed in cSCC CAFs and linked to immune and stromal regulation.

How does increased TDO2 expression affect CD8+ T-cell infiltration and tumor behavior?

High TDO2 expression correlates with reduced CD8+ T-cell infiltration, consistent with immune evasion. It is also associated with poorer tumor differentiation.

What is the effect of TDO2 inhibition on tumors and immune responses?

TDO2 inhibitors reduce tumor size and number in mice and effectively increase CD8+ T-cell infiltration. They also modulate immune cell activity and downregulate the PI3K-Akt signaling pathway.

Sep 23, 2026

Uploaded by Jiven