Transforming adoptive macrophages into living immune amplifiers with intracellular nanobatteries to potentiate tumor immunotherapy.

Abstract

Adoptive macrophage therapy holds great promise for solid tumor immunotherapy, but is often limited by poor phenotypic persistence and an inability to remodel the broader immunosuppressive tumor microenvironment (TME). Here, we report a Charged Macrophage (ChAR-M), a nanobattery-powered living immune amplifier, that enables sustained macrophage activation and TME immune remodeling. ChAR-M is generated by installing the intracellular nanobattery composed entirely of a redox-responsive dimer of the Toll-like receptor 7/8 agonist (R848) into macrophages. The nanobattery continuously releases immunostimulatory signals intracellularly, maintaining durable M1-like macrophage polarization and preventing tumor-associated macrophages (TAMs) re-education. Beyond cell-autonomous activation, ChAR-M functions as a living immune amplifier that propagates antitumor signals to surrounding TAMs through sustained secretion of pro-inflammatory cytokines and bioactive extracellular vesicles. This paracrine amplification rewires macrophage communication networks and drives cascading remodeling of immunosuppressive TME. Consequently, ChAR-M converts immunosuppressive tumors into immune-activating niches characterized by enhanced T-cell infiltration, reduced regulatory T-cell accumulation, suppressed angiogenesis, and inhibited metastatic progression. In breast cancer and melanoma mice models, ChAR-M elicited potent antitumor responses and significantly inhibited tumor progression. This work establishes intracellular nanobatteries as a general strategy for programming living immune amplifiers and provides a non-genetic platform for durable remodeling of the tumor immune microenvironment.