Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy, The Tianjin Key Laboratory of Biomaterials, Institute of Biomedical Engineering, Peking Union Medical College & Chinese Academy of Medical Sciences, Tianjin, 300192, China.
J Nanobiotechnology. 2024 Jun 18;22(1):341. doi: 10.1186/s12951-024-02622-1.
Tumor-associated macrophages (TAMs) are pivotal within the immunosuppressive tumor microenvironment (TME), and recently, have attracted intensive attention for cancer treatment. However, concurrently to promote TAMs repolarization and phagocytosis of cancer cells remains challenging. Here, a TAMs-targeted albumin nanoparticles-based delivery system (M@SINPs) was constructed for the co-delivery of photosensitizer IR820 and SHP2 inhibitor SHP099 to potentiate macrophage-mediated cancer immunotherapy. M@SINPs under laser irradiation can generate the intracellular reactive oxygen species (ROS) and facilitate M2-TAMs to an M1 phenotype. Meanwhile, inhibition of SHP2 could block the CD47-SIRPa pathway to restore M1 macrophage phagocytic activity. M@SINPs-mediated TAMs remodeling resulted in the immunostimulatory TME by repolarizing TAMs to an M1 phenotype, restoring its phagocytic function and facilitating intratumoral CTLs infiltration, which significantly inhibited tumor growth. Furthermore, M@SINPs in combination with anti-PD-1 antibody could also improve the treatment outcomes of PD-1 blockade and exert the synergistic anticancer effects. Thus, the macrophage repolarization/phagocytosis restoration combination through M@SINPs holds promise as a strategy to concurrently remodel TAMs in TME for improving the antitumor efficiency of immune checkpoint block and conventional therapy.
肿瘤相关巨噬细胞（TAMs）在免疫抑制性肿瘤微环境（TME）中起着关键作用，最近已成为癌症治疗的研究热点。然而，如何同时促进 TAMs 的重极化和对癌细胞的吞噬作用仍然具有挑战性。在这里，构建了一种基于肿瘤相关巨噬细胞靶向白蛋白纳米粒的递药系统（M@SINPs），用于共递送光敏剂 IR820 和 SHP2 抑制剂 SHP099，以增强巨噬细胞介导的癌症免疫治疗。在激光照射下，M@SINPs 可以产生细胞内活性氧（ROS），并促进 M2-TAMs 向 M1 表型转化。同时，抑制 SHP2 可以阻断 CD47-SIRPa 通路，恢复 M1 巨噬细胞的吞噬活性。M@SINPs 介导的 TAMs 重塑通过将 TAMs 重极化为 M1 表型，恢复其吞噬功能并促进肿瘤内 CTLs 的浸润，从而显著抑制肿瘤生长。此外，M@SINPs 联合抗 PD-1 抗体也可以改善 PD-1 阻断治疗的效果，发挥协同抗癌作用。因此，通过 M@SINPs 实现巨噬细胞重极化/吞噬功能恢复的联合策略有望成为一种同时重塑 TME 中 TAMs 的策略，以提高免疫检查点阻断和常规治疗的抗肿瘤效率。
