Mouse WT vsTSHR KO CD8+ T cell RNA sequencing

Dysfunction of CD8+ T cells in the tumor microenvironment (TME) is the main cause of tumor immune escape and immunotherapy tolerance. Tumor cells contribute to immunosuppression in the TME, but the specific mechanism in colorectal cancer (CRC) is still poorly understood. Here, we showed that thyroid stimulating hormone receptor (TSHR) played a pivotal role in regulating CD8+ T cell exhaustion in the TME of CRC. We identified TSH/TSHR signaling as the intrinsic pathway in regulating CD8+ T cell exhaustion. Conditional deletion of TSHR in CD8+ TILs improved effector differentiation and suppressed the expression of immune checkpoint receptors, such PD1 and Tim3. Moreover, CRC cells secreted TSHR via extracellular vesicles to increase the TSHR level in CD8+ T cells, resulting in immunosuppression in the TME. Low expression of TSHR in CRC was a predictor of immunotherapy response. On the other hand, we found that myeloid-derived suppressor cells (MDSCs) were the main source of TSH within the TME. Our findings highlight the role of endogenous TSH/TSHR signaling in CD8+ TILs in CRC and have important significance for the application of ICB therapies.