A Dual Stimuli-Responsive Nanoimmunomodulator for Antitumor Synergy of Macrophages and T Cells

Only a minority of patients benefit from current T-cell-focused adaptive immunotherapies, underscoring the need to engage innate immune cells, particularly macrophages, for multilayered tumor control. However, high-efficacy therapeutics capable of orchestrating multiple immune cells remain scarce. Herein, a dual stimuli-responsive nanoimmunomodulator (6EPP@si) that caters specifically to the tumor microenvironment (TME) is presented for the antitumor synergy of macrophages and T cells. Using the functional polymer-based carrier, we co-deliver the endoplasmic reticulum (ER)-localized photosensitizer 6E and small interfering RNA targeting CD47 (siCD47) into breast tumors. Within the acidic and high-glutathione TME, 6EPP@si undergoes self-lysosome escape and nanocleavage for precise, on-demand drug release. Consequently, siCD47 released into the cytoplasm enables potent CD47 silencing, while the ER-targeted photosensitizer 6E induces immunogenic cell death through reactive oxygen species-based ER stress, triggering the release of damage-associated molecular patterns, including calreticulin surface translocation. 6EPP@si enhances macrophage phagocytosis by modulating both antiphagocytic and prophagocytic signals and also promotes antigen presentation to activate T cells. In orthotopic breast tumor and spontaneous lung metastatic tumor models, this combined approach demonstrates robust antitumor effects and effective antimetastatic immunity, offering a meaningful strategy to simultaneously activate multiple immune cells for enhancing cancer immunotherapy.