Polymannose-Guided Repolarization of Tumor-Associated Macrophages for Enhanced Photodynamic Immunotherapy

Photodynamic immunotherapy has been recognized as a promising strategy for malignant tumor treatment, but its efficacy is still limited by the immunosuppressive tumor microenvironment (TME), particularly the dominance of M2-like tumor-associated macrophages (TAMs). To overcome this limitation, we constructed an acid-responsive, mannose-functionalized nanoplatform (FI@PMD) to target the TAMs. FI@PMD efficiently accumulates in tumors and is selectively internalized by M2-like macrophages via mannose-receptor-mediated recognition. Under acidic conditions, it undergoes structural disassociation, leading to the release of therapeutic components of a near-infrared photosensitizer (FBC) and the Toll-like receptor 7 (TLR7) agonist imiquimod (IMQ). Upon light irradiation, the released FBC could generate reactive oxygen species (ROS) that promote the polarization of TAMs from the M2 phenotype toward the M1 phenotype, thereby enabling immunosuppressive TME remodeling and enhancing photodynamic immunotherapy. In vitro studies demonstrated that FI@PMD is efficiently taken up by M2-like macrophages and induces their repolarization, accompanied by the upregulation of pro-inflammatory cytokines and the suppression of anti-inflammatory factors, resulting in inhibited tumor cell proliferation. In vivo experiments demonstrated that FI@PMD increased the infiltration of CD8⁺ cytotoxic T cells in tumor tissues to 2.85-fold of that in the PBS group while reducing the proportion of Treg cells to 0.86-fold. Collectively, this TAM-targeted reprogramming strategy provides a promising approach to overcome immunosuppressive TME and enhance the efficacy of photodynamic immunotherapy in malignant tumors.