Abstract：
We evaluated modulation of the immunosuppressive tumor microenvironment in both local and liver metastatic colorectal cancer (LMCC), focusing on tumor-associated macrophages, which are the predominant immunosuppressive cells in LMCC. We developed an orally administered metronomic chemotherapy regimen, oral CAPOX. This regimen combines capecitabine and a nano-micelle encapsulated, lysine-linked deoxycholate and oxaliplatin complex (OPt/LDC-NM). The treatment effectively modulated immune cells within the tumor microenvironment by activating the cGAS-STING pathway and inducing immunogenic cell death. This therapy modulated immune cells more effectively than did capecitabine monotherapy, the current standard maintenance chemotherapy for colorectal cancer. The macrophage-modifying effect of oral CAPOX was mediated via the cGAS-STING pathway. This is a newly identified mode of immune cell activation induced by metronomic chemotherapy. Moreover, oral CAPOX synergized with anti-PD-1 antibody (αPD-1) to enhance the T-cell-mediated antitumor immune response. In the CT26. CL25 subcutaneous model, combination therapy achieved a 91 % complete response rate with a confirmed memory effect against the tumor. This combination also altered the immunosuppressive tumor microenvironment in LMCC, which αPD-1 monotherapy could not achieve. Oral CAPOX and αPD-1 combination therapy outperformed the maximum tolerated dose for treating LMCC, suggesting metronomic therapy as a promising strategy.
摘要：
我们评估了局部和肝转移性结直肠癌（LMCC）中免疫抑制肿瘤微环境的调节，专注于肿瘤相关的巨噬细胞，它们是LMCC中主要的免疫抑制细胞。我们开发了一种口服节拍化疗方案，口服CAPOX。该方案结合了卡培他滨和纳米胶束封装，赖氨酸连接的脱氧胆酸盐和奥沙利铂复合物（OPT/LDC-NM）。该治疗通过激活cGAS-STING途径和诱导免疫原性细胞死亡来有效调节肿瘤微环境内的免疫细胞。这种疗法比卡培他滨单一疗法更有效地调节免疫细胞，目前标准的大肠癌维持化疗。口服CAPOX的巨噬细胞修饰作用是通过cGAS-STING途径介导的。这是新发现的由节拍化疗诱导的免疫细胞活化模式。此外，口服CAPOX与抗PD-1抗体（αPD-1）协同增强T细胞介导的抗肿瘤免疫应答。在CT26。CL25皮下模型，联合治疗获得了91%的完全缓解率,并且对肿瘤有明确的记忆效应.这种组合也改变了LMCC的免疫抑制肿瘤微环境，其中αPD-1单药治疗无法实现。口服CAPOX和αPD-1联合疗法优于治疗LMCC的最大耐受剂量，建议将节拍疗法作为一种有前途的策略。
