Responsive Photosensitizer Precursors Reverse Drug-Induced Secondary Immunosuppression

Pharmacological treatments, common methods for inhibiting tumor cell proliferation, often concurrently induce secondary immunosuppression. Reprogramming tumor-associated macrophages (TAMs) from an M2 to M1 phenotype via photosensitization offers a promising strategy to relieve the immunosuppressive tumor microenvironment, which may serve as an effective approach to reverse secondary immunosuppression. However, the efficacy of current photosensitizers is limited due to the insufficient macrophage specificity and suboptimal photosensitivity. To address these challenges, we here reported a proximity-driven strategy that optimizes the spatial positioning of photosensitizer precursors (PPs) relative to the active center of overexpressed enzymes, substantially enhancing the activation efficiency and selectivity of PPs in M2 macrophages. Simultaneously, through the integrated screening of photosensitizer performance, we developed a novel PP (NP-YB-5) that demonstrates superior efficacy (72.1%) in inducing macrophage polarization compared to both current immune adjuvants and earlier-generation responsive precursors (<60%). More importantly, phototherapy mediated by NP-YB-5 not only eliminates primary tumors exhibiting secondary immunosuppression but also inhibits the progression of distal (metastatic) tumors, achieving a statistical cure rate of 85%. Our work presents a novel design paradigm for the development of potent molecular tools in macrophage-mediated photosensitization, offering a promising approach for overcoming drug-induced secondary immunosuppression of tumors.