Two-pronged nanomedicine enhances immunotherapy by remodeling tumor metabolism

• Met-BsAb enhances intratumoral metformin delivery and immune checkpoint blockade. • This nanomedicine reprograms tumor metabolism and reverses immunosuppression. • Met-BsAb demonstrates potent anti-tumor efficacy and inhibits recurrence. • The strategy significantly prolongs survival in an H22 tumor model. Immune checkpoint inhibitor (ICI) therapy remains hindered by low response rates, largely due to the immunosuppressive tumor microenvironment (TME) and dysregulated tumor metabolism that jointly impair anti-tumor immunity. To address this key bottleneck, we rationally designed a dual-functional bispecific antibody nanomedicine (Met-BsAb) by loading metformin into Fc-binding peptide-grafted poly(L-glutamic acid) nanoparticles and conjugating anti-PD1/anti-LAG-3 antibodies. This material design enables targeted delivery of metformin to tumors and synchronous blockade of dual immune checkpoints. In a mouse H22 tumor model, Met-BsAb significantly enhanced intratumoral drug accumulation and penetration. Mechanistically, Met-BsAb remodeled the immunosuppressive TME by activating CD8 + T cells and reducing myeloid-derived suppressor cell infiltration, while reprogramming tumor metabolism via activation of the AMPK pathway and inhibition of the mTOR pathway. These coordinated effects synergistically boosted anti-tumor immunotherapy, induced long-term immune memory, and effectively suppressed tumor recurrence. This study provides a novel material-based strategy for synergistic immunometabolic regulation, offering a promising candidate to overcome ICI resistance in cancer treatment.