Cancer-associated fibroblasts metabolic targeting overcomes T-cell exclusion and chemoresistance [Human]

T cell-based immunotherapies have exhibited promising outcomes in tumor control; however, their efficacy is limited in immune-excluded tumors. Cancer-associated fibroblasts (CAFs) play a pivotal role in shaping the tumor microenvironment and modulating T cell infiltration. Despite the identification of distinct CAF subtypes using single-cell RNA-sequencing, their specific impact on hindering T cell infiltration remains unclear, particularly in soft-tissue sarcomas (STS) characterized by low response rates to T cell-based therapies. In this study, we comprehensively characterized the STS microenvironment using murine models with distinct immune composition and scRNA-seq, leading to the identification of a unique subset of CAFs termed glycolytic cancer-associated fibroblasts (glyCAFs). GlyCAFs rely on glycolysis to impede cytotoxic T cell infiltration into the tumor parenchyma. Targeting glycolysis in glyCAFs enhances T-cell infiltration and augments the efficacy of chemotherapy. These findings highlight new avenues for combinatorial therapeutic interventions in sarcomas and other solid tumors. Further investigations and clinical trials are needed to validate these potential strategies and translate them into clinical practice. Human sarcoma samples (n=1 tumor each Sample) from surgical resections were singly collected and processed for single-cell RNA sequencing.