Supramolecular copolymerized peptide self-assembly enables in situ reprogramming of tumor-associated macrophages to potentiate mild photothermal immunotherapy of cold tumors

The progressive advancement of nanomedicine has positioned mild photothermal therapy (mPTT) at the forefront of oncological research as a precision therapeutic modality with spatiotemporal controllability. Unlike conventional photothermal ablation, mPTT operates under finely regulated thermal conditions that minimize collateral damage to peritumoral tissues while preserving immune cell viability through avoidance of hyperthermia-induced apoptosis. Nevertheless, the therapeutic potential of mPTT remains constrained by inherent challenges such as the persistently immunosuppressive tumor microenvironment (TME) and the subablative thermal conditions that allow residual malignant cell survival. To address these limitations, we developed a TME-responsive supramolecular platform through the rational design of copolymerized peptides capable of self-assembling with both a near-infrared photosensitizer and an immune modulator. This nanoconstruct leverages noncovalent molecular interactions, primarily governed by π-π stacking, to achieve stable co-loading of therapeutic payloads. The resultant nanoplatform demonstrates robust immunomodulatory capacity, effectively remodeling the immunosuppressive tumor milieu through repolarization of tumor-associated macrophages from a protumoral M2 phenotype to an antitumoral M1 states. Concomitantly, the system induces immunogenic cell death through photothermal-associated mechanisms, leading to the generation of tumor-specific damage-associated molecular patterns (DAMPs) under mild hyperthermic conditions. Crucially, our findings reveal that M1-reprogrammed macrophages collaborate with DAMPs-activated dendritic cells to establish a cooperative antigen presentation axis, forming an immunostimulatory relay that overcomes the dual challenges of T-cell exclusion and antigenic silence characteristic of immunologically "cold" tumors. This coordinated immunologic cascade drives substantial intratumoral infiltration of effector T lymphocytes while sustaining favorable activation profiles, effectively converting immune-deserted neoplasms into immunologically responsive lesions. STATEMENT OF SIGNIFICANCE: In this study, we report the rational design and synthesis of a supramolecular copolymerized peptide based on aromatic amino acids, which self-assembles into stable nanostructures through dominant π-π stacking and other intermolecular interactions. The resulting nanoplatform exhibits strong responsiveness to the tumor microenvironment (TME) and enables efficient co-loading of both a photosensitizer and an immunomodulator. This allows for controlled mild photothermal therapy (mPTT), which effectively induces immunogenic cell death (ICD) while minimizing collateral damage to surrounding healthy tissues. More importantly, the system actively reprograms tumor-associated macrophages (TAMs) within the TME, thereby remodeling the immunosuppressive microenvironment and amplifying ICD-driven antitumor immune responses. This work provides a new paradigm for the development of multifunctional nanomaterials in synergistic photothermal-immunotherapy, particularly for addressing immunologically "cold" tumors that are unresponsive to conventional therapy.