Nano-immunomodulator amplifies STING activation in tumor-associated macrophages for cancer immunotherapy

The initiation of tumor-specific T cell responses is critically dependent on antigen-presenting cells (APCs). Nevertheless, as the most dominant APCs in tumors, M2-like macrophages largely restrained T cell activation due to inefficient antigen cross-presentation. Herein, we rationally designed a nano-immunomodulator (FANP) to restore the antigen presentation capability of M2-like macrophages by amplifying stimulator of interferon genes (STING) activation. FANPs were fabricated by self-assembly of Fe³⁺ and Raddeanin A (RA), which rapidly degraded when reaching tumor microenvironment. The released Fe³⁺ induced the polarization of M2-like macrophages into M1 phenotype, followed by RA stimulation for amplified STING activation, allowing robust antigen cross-presentation and T cell-driven anti-tumor response, leading to effective tumor regression in both immunogenic and poor-immunogenic tumor models. Notably, FANPs exhibited intensive STING activation in human tumor samples, showing potential for clinical impact. Our work offers a simple and robust strategy to re-educate M2-like macrophages by augmenting STING activation for cancer immunotherapy.