A supramolecular peptide reprograms PD-L1⁺ tumor-associated macrophages to enhance antitumor immunity in lung adenocarcinoma

Despite advances in immune checkpoint inhibitors (ICIs), clinical benefit in lung adenocarcinoma (LUAD) remains limited, largely due to a highly immunosuppressive tumor immune microenvironment (TIME). Tumor-associated macrophages (TAMs), particularly the PD-L1–positive subset (PD-L1⁺ TAMs), are key mediators of this immunosuppression, yet their functional roles and therapeutic targetability in LUAD are not fully defined. Through integrated analysis of multiplex immunohistochemistry from ICI-treated LUAD patients and public single-cell RNA sequencing data, we identified PD-L1⁺ TAMs as an M2-polarized population enriched in non-responders and associated with CD8⁺ T-cell exhaustion and poor overall survival. To address this, we engineered MH-PDBP, a supramolecular peptide nanoplatform via aurophilic self-assembly, coated with mannosylated human serum albumin for selective TAM targeting. Mechanistically, MH-PDBP was preferentially internalized by M2-like macrophages through clathrin-dependent endocytosis, promoting lysosomal degradation of PD-L1, thereby reprogramming macrophages toward an M1 phenotype and enhancing their phagocytic activity. In an orthotopic LUAD mouse model, MH-PDBP monotherapy significantly reduced tumor burden, decreased intratumoral PD-L1⁺ TAMs, and increased cytotoxic T-lymphocyte infiltration, thereby reinvigorating systemic antitumor immunity. When combined with radiotherapy, MH-PDBP further improved local tumor control, suppressed tumor growth, and remodeled the TIME toward a proinflammatory state without incurring additional systemic toxicity. These findings establish PD-L1⁺ TAMs as a druggable mediator of immunosuppression in LUAD and propose supramolecular peptide–mediated macrophage reprogramming as a translatable strategy for enhancing antitumor immunity and guiding the rational design of combination therapies.