纳米粒子与肿瘤靶向细菌的结合用于癌症免疫治疗，可以克服纳米粒子积累性差、渗透性有限、分布受限的缺点。然而，通过同时可控地调节免疫细胞和肿瘤细胞来提高治疗效果，对于混合系统来说仍然是一个巨大的挑战。在此，合理设计了混合治疗平台以实现免疫级联增强的癌症免疫治疗。为了构建杂交体，对第二近红外 (NIR-II) 区域的光响应的光热纳米颗粒通过 pH 响应席夫碱键结合到工程细菌的表面。利用细菌的缺氧靶向和深度渗透特性，杂交体可以在肿瘤部位积累。然后纳米粒子与细菌分离，实现肿瘤细胞的基因工程，诱导肿瘤细胞凋亡并下调程序性细胞死亡配体1的表达，从而缓解免疫抑制的肿瘤微环境。温和的光热加热不仅可以诱导肿瘤相关抗原的释放，还可以触发细胞因子白细胞介素2的持续表达。值得注意的是，p53转染过程和NIR-II光激活细菌基因工程之间实现了协同抗肿瘤作用。这项工作提出了一种构建混合系统以实现级联增强癌症免疫治疗的简便策略。© 2024 Wiley‐VCH GmbH。

The combination of nanoparticles and tumor-targeting bacteria for cancer immunotherapy can overcome the shortcomings of poor nanoparticle accumulation, limited penetration, and restricted distribution. However, it remains a great challenge for the hybrid system to improve therapeutic efficacy through the simultaneous and controllable regulation of immune cells and tumor cells. Herein, a hybrid therapeutic platform is rationally designed to achieve immune cascade-augmented cancer immunotherapy. To construct the hybrids, photothermal nanoparticles responsive to light in the second near-infrared (NIR-II) region are conjugated onto the surface of engineered bacteria through pH-responsive Schiff base bonds. Taking advantage of the hypoxia targeting and deep penetration characteristics of the bacteria, the hybrids can accumulate at tumor sites. Then nanoparticles detach from the bacteria to realize genetic engineering of tumor cells, which induces tumor cell apoptosis and down-regulate the expression of programmed cell death ligand 1 to alleviate immunosuppressive tumor microenvironment. The mild photothermal heating can not only induce tumor-associated antigen release, but also trigger sustainable expression of cytokine interleukin-2. Notably, a synergistic antitumor effect is achieved between the process of p53 transfection and NIR-II light-activated genetic engineering of bacteria. This work proposes a facile strategy for the construction of hybrid system to achieve cascade-augmented cancer immunotherapy.© 2024 Wiley‐VCH GmbH.