Advanced cutaneous squamous cell carcinoma has been transformed by anti-PD-1 immunotherapy, yet roughly half of patients with the disease fail to respond to treatment. A new study published in Cancer Immunology, Immunotherapy set out to understand why, by examining the molecular features of tumors before therapy begins and searching for markers that could predict which patients will benefit. The researchers report that both immune-related and tumor-intrinsic gene signatures are associated with resistance and response to PD-1 blockade, offering candidate biomarkers that now require validation in larger independent cohorts.
The team, led by Viola K. DeTemple, Maximilian Beikirch and colleagues under senior author Katrin Schaper-Gerhardt, used whole transcriptome profiling with HTG EdgeSeq technology on pre-treatment tumor samples from patients with advanced cutaneous squamous cell carcinoma. Clinical data and treatment outcomes were then correlated with the gene expression profiles. Differentially expressed genes were analyzed in relation to response, and promising targets were further examined at the protein level using immunofluorescence and immunohistochemistry.
The results revealed a clear transcriptional divide between tumors that responded and those that did not. Tumors from patients achieving disease control showed a distinct immune-active profile, characterized by interferon-associated signaling, enhanced antigen presentation pathways and cytotoxic immune activity. Consistent with this, interferon-gamma and cytolytic activity signatures were higher in patients with favorable clinical outcomes.
To characterize the immune landscape more precisely, the researchers applied CIBERSORTx-based deconvolution, a computational method that estimates the composition of immune cell populations from bulk gene expression data. This analysis demonstrated marked interpatient heterogeneity, with T cells, macrophages and NK cells representing major components of the immune infiltrate. Notably, however, no major differences in overall immune cell composition were found between patients who progressed early and those who progressed late or not at all.
The most striking discovery came from the tumor cells themselves. Elevated gene expression of SLC7A5 and SOX2 was associated with poor response and early progression.
Importantly, the protein-level analyses supported the gene expression findings. Higher SLC7A5 expression was associated with early progression when assessed by immunofluorescence and immunohistochemistry. SOX2 showed a more heterogeneous pattern, with particularly high expression observed in a subset of progressive tumors.
The authors describe their findings as hypothesis-generating evidence. The study was conducted on a limited number of pre-treatment samples, and the associations between gene signatures and clinical outcomes, while consistent across transcriptional and protein-level analyses, were not validated in an external cohort. The researchers explicitly state that the identified markers require validation in larger independent cohorts before they can be considered for clinical use.
The work also highlights the complexity of immunotherapy resistance in this cancer type. The full open-access article, published on 30 October 2026, is available in Cancer Immunology, Immunotherapy.
Subject of Research: Biomarkers of response and resistance to PD-1 blockade immunotherapy in advanced cutaneous squamous cell carcinoma
Article Title: Immune and tumor-intrinsic signatures are associated with resistance and response to PD-1 blockade in cutaneous squamous cell carcinoma
Article References: DeTemple, V. K., Beikirch, M., Ulama, A. C., Bergmann, M., Bredemeier, S., Schacht, V., Sachse, M., Mohr, P., Gambichler, T., Gutzmer, R., & Schaper-Gerhardt, K. (2026). Immune and tumor-intrinsic signatures are associated with resistance and response to PD-1 blockade in cutaneous squamous cell carcinoma. Cancer Immunology, Immunotherapy. https://doi.org/10.1007/s00262-026-04610-w
Image Credits: AI Generated
DOI: 10.1007/s00262-026-04610-w
Keywords: cutaneous squamous cell carcinoma, PD-1 blockade, immunotherapy resistance, biomarkers, SLC7A5, SOX2, interferon signaling, tumor microenvironment, transcriptomics, CIBERSORTx, immune infiltration, cancer immunology
News Source: Nathaniel Bowman. (October 30, 2026). Gene Signatures Linked to Resistance and Response to PD-1 Blockade in Skin Cancer. Scienmag.
