The response rate of anti-PD therapy in most cancer patients remains low. Therapeutic drug and tumor-infiltrating lymphocytes (TILs) are usually obstructed by the stromal region within tumor microenvironment (TME) rather than distributed around tumor cells, thus unable to induce the immune response of cytotoxic T cells. Here, we constructed the cationic thermosensitive lipid nanoparticles IR780/DPPC/BMS by introducing cationic NIR photosensitizer IR-780 iodide (IR780) modified lipid components, thermosensitive lipid DPPC and PD-1/PD-L1 inhibitor BMS202 (BMS). Upon laser irradiation, IR780/DPPC/BMS penetrated into deep tumor, and reduced cancer-associated fibroblasts (CAFs) around tumor cells to remodel the spatial distribution of TILs in TME. Interestingly, the cationic IR780/DPPC/BMS could capture released tumor-associated antigens (TAAs), thereby enhancing the antigen-presenting ability of DCs to activate cytotoxic T lymphocytes. Moreover, IR780/DPPC/BMS initiated gel-liquid crystal phase transition under laser irradiation, accelerating the disintegration of lipid bilayer structure and leading to the responsive release of BMS, which would reverse the tumor immunosuppression state by blocking PD-1/PD-L1 pathway for a long term. This combination treatment can synergistically exert the antitumor immune response and inhibit the tumor growth and metastasis.

大多数癌症患者的抗 PD 治疗反应率仍然很低。治疗药物和肿瘤浸润淋巴细胞（TILs）通常被肿瘤微环境（TME）内的基质区域阻塞，而不是分布在肿瘤细胞周围，因此无法诱导细胞毒性T细胞的免疫反应。在这里，我们通过引入阳离子近红外光敏剂 IR-780 碘化物 (IR780) 修饰的脂质成分、热敏脂质 DPPC 和 PD-1/PD-L1 抑制剂 BMS202 (BMS) 构建了阳离子热敏脂质纳米颗粒 IR780/DPPC/BMS。激光照射后，IR780/DPPC/BMS 深入肿瘤深处，减少肿瘤细胞周围的癌相关成纤维细胞 (CAF)，从而重塑 TME 中 TIL 的空间分布。有趣的是，阳离子 IR780/DPPC/BMS 可以捕获释放的肿瘤相关抗原 (TAA)，从而增强DCs激活细胞毒性T淋巴细胞的抗原呈递能力。此外，IR780/DPPC/BMS在激光照射下引发凝胶-液晶相变，加速脂质双层结构的解体，导致BMS的响应性释放，通过阻断PD-1/PD-L1逆转肿瘤免疫抑制状态长期的途径。这种联合治疗可以协同发挥抗肿瘤免疫反应，抑制肿瘤生长和转移。这将通过长期阻断PD-1/PD-L1通路来逆转肿瘤免疫抑制状态。这种联合治疗可以协同发挥抗肿瘤免疫反应，抑制肿瘤生长和转移。这将通过长期阻断PD-1/PD-L1通路来逆转肿瘤免疫抑制状态。这种联合治疗可以协同发挥抗肿瘤免疫反应，抑制肿瘤生长和转移。