免疫疗法，包括细胞养护治疗 (ACT) 和免疫检查点抑制剂 (ICIs)，对大多数结直肠癌 (CRC) 患者的疗效有限，对肝脏转移患者的效果进一步受限。缺乏抗肿瘤淋巴细胞浸润可能是主要原因，因此急需更强效和更安全的 CRC 治疗方法。本研究全面评估了低分子量肝素 (LMWH) 与免疫疗法在微卫星稳定 (MSS) 高攻击性小鼠 CRC 模型中的抗肿瘤协同作用。双重应用 LMWH 和 ACT 显著抑制了肿瘤生长的停滞和肝脏转移的抑制，而单独应用 LMWH 或 ACT 对其无任何抗肿瘤活性。LMWH 与 ACT 的联合应用明显增加了肿瘤内 CD8+ T 细胞的浸润，通过多重免疫组织化学、纯化的 CD8+ T 细胞转移实验和 IVIM 体内成像进一步证实。从机制上看，肿瘤微环境变化评估表明，LMWH 改善了肿瘤血管正常化，促进了活化的 CD8+ T 细胞进入肿瘤。类似地，在小鼠 CT26 肿瘤模型中，LMWH 与抗程序性细胞凋亡蛋白 1 (PD-1) 疗法相比，提供了更强大的抗肿瘤活性。LMWH 可以通过增加淋巴细胞浸润到肿瘤中，尤其是细胞毒性 CD8+ T 细胞，增强 ACT 和 ICIs 基于免疫疗法的效果。以上结果表明，将 LMWH 与免疫疗法策略结合是结直肠癌治疗的一种有前景且安全的方法，尤其是对于 MSS 肿瘤。© 作者（或其雇主）2023年。 在 CC BY-NC 下允许再利用。不得用于商业目的。请参阅权利和权限。由 BMJ 出版。

Immunotherapy, including adoptive cell therapy (ACT) and immune checkpoint inhibitors (ICIs), has a limited effect in most patients with colorectal cancer (CRC), and the efficacy is further limited in patients with liver metastasis. Lack of antitumor lymphocyte infiltration could be a major cause, and there remains an urgent need for more potent and safer therapies for CRC.In this study, the antitumoral synergism of low molecular weight heparin (LMWH) combined with immunotherapy in the microsatellite stable (MSS) highly aggressive murine model of CRC was fully evaluated.Dual LMWH and ACT objectively mediated the stagnation of tumor growth and inhibition of liver metastasis, neither LMWH nor ACT alone had any antitumoral activity on them. The combination of LMWH and ACT obviously increased the infiltration of intratumor CD8+ T cells, as revealed by multiplex immunohistochemistry, purified CD8+ T-cell transfer assay, and IVIM in vivo imaging. Mechanistically, evaluation of changes in the tumor microenvironment revealed that LMWH improved tumor vascular normalization and facilitated the trafficking of activated CD8+ T cells into tumors. Similarly, LMWH combined with anti-programmed cell death protein 1 (PD-1) therapy provided superior antitumor activity as compared with the single PD-1 blockade in murine CT26 tumor models.LMWH could enhance ACT and ICIs-based immunotherapy by increasing lymphocyte infiltration into tumors, especially cytotoxic CD8+ T cells. These results indicate that combining LMWH with an immunotherapy strategy presents a promising and safe approach for CRC treatment, especially in MSS tumors.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.