Spatial Transcriptomic Profiling of FAP-Positive Cells in Gastric Cancer and Association with Immunotherapy Efficacy

Tashireva, Liubov A.; Kalinchuk, Anna Yu.; Shmakova, Elena O.; Tsarenkova, Elisaveta A.; Vtorushin, Sergey V.; Zelchan, Roman V.; Grigoryeva, Evgeniya S.; Larionova, Irina V.

doi:10.31557/APJCP.2026.27.10.3619

Spatial Transcriptomic Profiling of FAP-Positive Cells in Gastric Cancer and Association with Immunotherapy Efficacy

Document Type : Research Articles

Authors

Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia.

10.31557/APJCP.2026.27.10.3619

Abstract

Introduction: The spatial heterogeneity of the tumor microenvironment in gastric cancer, particularly in the stromal compartment, remains poorly characterized. Fibroblast activation protein (FAP)-positive cancer-associated fibroblasts (CAFs) are known to promote tumor progression, immune evasion, and therapeutic resistance. However, the spatial transcriptional programs of FAP+ and FAP- stroma and their associations with response to immunotherapy are not fully understood. Material and methods: Formalin-fixed, paraffin-embedded (FFPE) gastric cancer tissue sections were analyzed with the 10x Genomics Visium Spatial Gene Expression platform, and IHC was used to validate the transcriptional findings. Results: The FAP+ stromal regions displayed a transcriptional profile characterized by extensive extracellular matrix remodeling (COL1A1, FN1, SPARC), immunosuppressive signaling (GREM1, C1S, IFI44), and high expression of canonical CAF markers (ACTA2, TAGLN). In contrast, FAP- regions retained epithelial features, indicating a closer proximity to tumor cells, and showed enrichment in antigen presentation and interferon signaling pathways. Pathway analysis confirmed the divergence in functional states between these stromal regions. Importantly, FAP+ regions in non-responders to immunotherapy exhibited overexpression of fibrosis- and stemness-associated genes, along with immunosuppressive chemokines (CCL20/28), whereas responders demonstrated robust interferon signaling, antigen processing, and epithelial differentiation. Expression of CD24 in fibroblasts was validated by immunohistochemistry, confirming transcriptomic data and suggesting potential new drug targets in tumor stroma. Conclusion: FAP+ regions, in contrast to FAP- clusters, exhibited dense fibrosis, distinct metabolic profiles, and altered immune signatures. Non-responders to immunotherapy displayed a fibrotic, immunosuppressive FAP+ signature associated with stemness and radioresistance, supporting the use of combined FAP-targeted radionuclide therapy with radiosensitizers. Conversely, responders’ FAP+ niches showed immune activation and interferon signaling, favoring immunomodulatory treatments.

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