Tumor Microenvironment Responsive Nano-Immunoregulator for Precision Cancer Photodynamic Immunotherapy

Spatiotemporally controlled reactive oxygen species (ROS) generation remains pivotal for advancing photodynamic immunotherapy. Herein, we present tumor microenvironment (TME)-responsive nano-immunoregulator featuring a CaCO 3 shell encapsulating a mesoporous silica core modified with folic acid/chlorin e6 (FA/Ce6) and co-loaded with dBET6 and maleimide (MA). Acidic TME triggers CaCO 3 shell degradation, neutralizing tumor acidity to repolarize macrophages toward M1 type, enhancing antigen presentation and T cells immune response while exposing the BM@M FC core. The resulting BM@M FC further endocytosed by tumor cells via FA-mediated tumor targeting, followed by MA-mediated glutathione depletion amplifies Ce6-generated ROS for potent photodynamic therapy (PDT). Concurrently, dBET6 degrades BRD4 to inhibit metastasis, downregulate PD-L1, and synergize with PDT to induce immunogenic cell apoptosis, thereby activating dendritic cells (DCs) and T cells for enhanced photodynamic immunotherapy. Both in vitro / vivo results indicate that BM@M FC C have excellent performance to inhibit primary/metastatic tumors, while single-cell RNA sequencing elucidates BM@M FC C can induce immunosuppressive TME remodeling, including increased CD8 + T cells, cDCs, and NK cells; M2-to-M1 macrophage polarization; and enhanced intercellular communication. Tumor cell profiling confirms BM@M FC C will downregulate oncogenic pathways and activate immune signatures. Collectively, this TME responsive nano-immunoregulator demonstrates superior therapeutic outcomes and provides a promising strategy for precision cancer photodynamic immunotherapy. The BM@M FC C are able to efficiently and precisely generate ROS in tumor to activate PDT and inhibit tumor metastasis, which further induce apoptosis for primary tumor elimination and produce TAAs for activating anti-tumor photodynamic immunotherapy. In addition, the dBET6 induces BRD4 degradation synergistically enhance apoptosis, metastasis inhibition, and reduce PD-L1 expression. Meanwhile, the local pH increase in tumor tissue promotes M2-to-M1 macrophage polarization, causing additional direct tumor cell killing, activating antigen-presenting immune responses, and enhancing anti-tumor immunity through inflammatory cytokine secretion.