抗肿瘤T细胞功能障碍影响免疫监视功能，促进肿瘤发生和进展。Ca2+-NFAT通路直接调控T细胞抑制性受体表达和功能状态。离子通道TRPV1可通过调控细胞内Ca2+信号影响T细胞活化。我们前期发现：TRPV1在人结直肠癌肿瘤间质中高表达，且与肿瘤进展有关。TRPV1功能增强后促进小鼠结直肠癌发生和进展，并影响肿瘤组织中CD8+T细胞的数量和抑制性受体表达。由此推测：结直肠癌中TRPV1通过Ca2+-NFAT通路促进抗肿瘤T细胞功能障碍和免疫逃逸。本研究拟探讨TRPV1功能改变对小鼠结直肠癌肿瘤组织中T细胞数量和功能的影响及与肿瘤进展的关系；证实TRPV1通过Ca2+-NFAT通路促进活化T细胞耗竭，诱导免疫逃逸。研究TRPV1对T细胞抑制性受体表达及对抗PD1单抗疗效的影响，阐明是否可通过抑制TRPV1而增强抗PD1单抗效果，验证二者联合应用的协同作用。为探寻结直肠癌免疫治疗新策略提供依据。

In the tumor microenvironment, antitumor T cells show a dysfunctional state, referred to as exhaustion, which impairs immunosurveillance and drives immune escape. The upregulation of inhibitory receptors such as PD1 is one of the hallmarks of T cell exhaustion. The transcription factor NFAT (nucler factor of activated T cells) controls the program of T cell exhaustion by regulating the expression of key inhibitory receptors. There is a direct role for Ca2+ signals in regulating NFAT activity and T cell function. Transient receptor potential vanilloid 1 (TRPV1) is functionally expressed in CD4+ and CD8+ T cells, where it acts as a Ca2+ channel and contributed to T cell antigen receptor (TCR)-induced Ca2+ influx and T cell activation. However, its role in T cell exhaustion within the tumor microenvironment is largely unknown. Our previous studies have shown that TRPV1 expression was significantly increased in human colorectal cancer tissues as compare with the adjacent tissues. Moreover, high TRPV1 expression in the stromal compartments was associated with metastases and tumor progression. By using a novel TRPV1 gain-of-function model (Trpv1G564S+/+), we found that TRPV1 hyperactivation significantly promoted AOM/DSS induced tumorigenesis in mice. Meanwhile, TRPV1 gain-of-function promoted tumor growth in MC38 tumor-bearing mice. Notably, the intratumoral T cells in Trpv1G564S+/+ mice exhibited a dysfunctional states, with a higher frequency of PD1+CD8+ and TIM3+CD8+ T cells as compared with wild type littermates. We therefore speculate that TRPV1 hyperactivation promotes T cell dysfunction and leads to immune escape in colorectal cancer. In this study, we will investigate the in vivo effects of TRPV1 on T cell function in models of AOM/DSS-induced cancer and MC38 tumor-bearing mice to examine if an immunomodulatory effect accompanies tumor progresssion, with a particular focus on its ability to modulate T cell exhaustion and immune escape. In addition, we aim to identify the molecular mechanism by which TRPV1 regulates T cell activation and exhaustion in the tumor microenvironment, with a special particular emphasis on whether TRPV1 exerts its effects through interfering with the Ca2+-NFAT pathway. Furthermore, we will elucidate the impact of TRPV1 on the response to PD1 bolckade in multiple in vivo syngeneic models, thereby providing a rationale for combining TRPV1 inhibitors and immunotherapies. Our results will define previously unrecognized immunomodulatory functions of TRPV1 in the tumor microenvironment. Furthermore, our study highlights the importance of identifying complementary strategies to improve the efficacy of immunotherapy for colorectal cancer.