Abstract 5295: Tumor stromal fibroblasts constitute a biological immune barrier by inducing instant immune cell death

Abstract The majority of low immune-reactive ‘cold’ tumors present an immune-excluded phenotype and it was proposed that stromal fibroblasts together with their collagen products constitute a physical barrier precluding lymphocytic infiltration into tumors. Here, we demonstrated a histopathological structure characterized by stromal fibroblasts embedded with dead lymphocytes in ‘cold’ tumors, named Crab-Nebula sign (CNs), indicating poor patient prognosis. Moreover, we identified a unique fibroblast subset in CNs-enriched structures overexpressing a sulfotransferase which triggers instant activation-induced cell death (AICD) in CTLs and NK cells. Mechanistically, we reveal that sulfonated HSPG receptor on activated immunocytes engaged by sulfonated HSPG inhibit p38-MAPK activation and reduce PI9 expression, leading to Granzyme B release into the cytosol and GSDME cleavage. Furthermore, sulfotransferase-knockout in fibroblasts or blocking sulfonated HSPG receptor in CTLs enhances anti-tumor effects of immune cell therapy in vivo. Collectively, we revealed that stromal fibroblasts construct a toxic biological barrier in ‘cold’ tumors and highlighted the therapeutic potential of disrupting the interaction between stromal fibroblasts and immunocytes in turning ‘immune-cold’ tumors hot. Citation Format: Jianing Chen, Wenfeng Zeng, Penghan Huang, Erwei Song. Tumor stromal fibroblasts constitute a biological immune barrier by inducing instant immune cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5295.