基于肿瘤死亡释放信号CXCL1exo/TAMs/PD-L1探讨癌毒塑造乳腺癌免疫抑制微环境的科学内涵

癌毒是中医药防治肿瘤病机理论的重大创新。肿瘤死亡释放信号是癌毒的一种，具有介导免疫抑制微环境并诱导复发转移的潜在作用，解析肿瘤死亡释放信号将挑战传统的“杀死性”治疗策略。我们前期证实乳腺癌化疗致死细胞释放的外泌体CXCL1exo信号能通过TAMs/PD-L1通路构建免疫抑制微环境继而促进转移发生，而消癖方可靶向CXCL1exo/TAMs通路抑制乳腺癌肺转移，由此设想消癖方可通过抑制肿瘤死亡释放信号CXCL1exo/TAMs/PD-L1阻断免疫抑制微环境构建，从而抑制转移发生。本研究拟通过活体细胞转移示踪、体内外基因修饰、细胞免疫功能、临床标本检测及高通量报告基因筛选等技术探讨CXCL1exo/TAMs/PD-L1轴诱导乳腺癌免疫抑制微环境构建的分子机制及中医药干预价值，以此丰富癌毒理论并阐释其塑造免疫抑制微环境的科学内涵，改变肿瘤还原治疗观念，提供干预肿瘤死亡释放信号和药物开发的新策略。

Cancer toxin theory is a great innovation of traditional Chinese Medicine for cancer prevention and treatment. The signals released by cancer dying cells were considered as one kind of cancer toxins. Recent studies demonstrated that the dying cancer cell-released signals could promote the formation of tumor immune suppression microenvironment and finally result in recurrence or metastasis. Molecular elucidation of the dying signals-mediated immune imbalance would be a great challenge to the traditional “cancer killing” therapeutic strategy. Our previous findings suggested that breast cancer dying cells-released exosomes could activate TAMs/PD-L1 via CXCL1exo, and subsequently establish immune suppressive microenvironment to promote cancer recurrence or metastasis. However, XIAOPI formula could inhibit CXCL1exo/TAMs signaling to inhibit breast cancer lung metastasis. Based on previous findings, we hypothesized that XIAOPI formula might inhibit the dying signaling CXCL1exo/TAMs/PD-L1 to block the formation of immune suppressive microenvironment and subsequent metastasis. Our study is designed to explore the biological and therapeutic significance of CXCL1exo/TAMs/PD-L1 axis in mediating cancer immune suppression and metastasis by utilizing in vivo metastasis tracking system, gene recombination technology, cellular immune function test, clinical biopsy detection and high-throughput gene reporting system. Our study will enrich the scientific value of cancer toxin theory and clarify its critical effects in mediating the establishment of cancer immune suppression microenvironment. Our findings would challenge the traditional reductive concept of Western Medicine. Meanwhile, our study will also provide novel strategy for the intervention of cancer dying cells-released signals and drug discovery.