TGFβ signaling activation correlates with immune-inflamed tumor microenvironment across human cancers and predicts response to immunotherapy.

Considering the determining role of TGFβ signaling in the tumor microenvironment (TME) on immune evasion, the inhibition of signaling is expected to enhance the therapeutic efficacy of immunotherapies, especially immune checkpoint blockade (ICB), which is confirmed in preclinical data. However, successive failures in clinical translation occur at the initial stage. To provide a better understanding of TGFβ signaling within the TME and its relation to the individual immunological status, we performed a pan-cancer analysis comparing the activation of TGFβ pathway among different TMEs based on multi-omics data. Compared with non-inflamed tumors, increased TGFβ signaling activity appeared in four non-cancer cell types within TME in inflamed tumors. Significant correlations were revealed between TGFβ signaling and reliable biomarkers for ICB therapy, as well as between TGFβ signaling and HPV status. Our findings contribute to explain the inconsistency between preclinical and clinical research, and are crucial to optimizing upcoming clinical trial design and improving patient stratification for personalized prediction.