TIM3介导的效应T细胞重度耗竭在肿瘤抗PD1治疗耐药中发挥重要作用，而抑制IFNG-JAK-STAT1信号通路可阻断抗PD1治疗耐药。我们从清热解毒类中药酸浆中发现新型JAK抑制剂酸浆内酯B，其抑制IFNG-JAK-STAT1-CEACAM1通路，减少TIM3+T细胞比例。基于此，我们提出酸浆内酯B抑制IFNG-JAK-CEACAM1通路阻断TIM3介导的胃癌PD1抗体治疗耐药的科学假设。围绕该假设，我们应用人源化NSGTM小鼠胃癌模型、原位邻位连接分析等技术：⑴揭示酸浆内酯B抑制IFNG-JAK-STAT1-CEACAM1通路的作用机制；⑵阐明酸浆内酯B下调CEACAM1抑制TIM3介导效应T细胞重度耗竭的分子机制；⑶明确酸浆内酯B协同PD1抗体免疫清除胃癌的作用机理。通过本项目研究，不仅为两者联合用药的研发和临床应用提供科学依据，而且为中医药肿瘤免疫治疗提供新思路。

TIM3-mediated severe T-cell exhaustion is the main mechanism of anti-PD1 cancer immunotherapy resistance. Recent studies have shown that inhibition of IFNG-JAK-STAT1 pathway antagonizes the severe T-cell exhaustion that causes acquired resistance to anti-PD1 immunotherapy. Our group discovered a novel JAK inhibitor Physapubescin B (PB) from Chinese herb Physalis alkekengi (a traditional clearing heat and detoxification Chinese medicine). Our preliminary data suggested PB reduced TIM3(+) T cells, a severe T-cell exhaustion sub-population, through inhibiting IFNG-JAK-STAT1-CEACAM1 pathway. We then hypothesize that PB may block TIM3-mediated resistance to anti-PD1 immunotherapy in gastric cancer by repressing the IFNG-JAK-CEACAM1 signaling. We plan to apply technologies such as humanized NSGTM mouse models with gastric cancer xenografts and in situ proximity ligation assay to test this hypothesis. In our proposal, we aim to: (1) clarify the mechanism of PB inhibition of IFNG-JAK-STAT1-CEACAM1 signaling; (2) clarify the molecular mechanism underling how PB inhibits TIM3-mediated severe T-cell exhaustion through CEACAM1 repression; (3) clarify the mechanism of synergistic effect of PB and anti-PD1 immunotherapy for the immune elimination of gastric cancer cells. Our research will not only lay the scientific foundation for the clinical application of such combination therapy, but also provide new direction for future studies on Chinese traditional medicine for cancer immunotherapy.