NIR-activated endoplasmic reticulum stress amplifier to regulate phagocytosis for macrophage-mediated cancer immunotherapy

Effectively activating macrophages to engulf tumor cells has attracted intensive attention in cancer immunotherapy. However, tumor cells can upregulate anti-phagocytic signals (such as CD47 molecules) to bind with signal regulatory protein-α (SIRPα), ultimately providing a “don’t eat me” signal to evade phagocytosis. Blockading CD47 alone is insufficient to stimulate macrophages phagocytosis due to the absence of endogenous activating signals (“eat me” signal). Herein, a mesoporous silica (MSN) modified by Cu 9 S 5 nanoparticle with mimicking enzyme activities were synthesized and utilized to electrostatically load the anti-CD47 antibodies (aCD47), generating MCC nanozymes, to improve macrophage-mediated cancer immunotherapy. MCC nanozymes can target tumor cells by specifically binding to the cell-surface CD47, disabling the “don’t eat me” signal. Meanwhile, under near infrared light (1064 nm) stimulation, MCC nanozymes exhibit the enhanced glutathione oxidase-like and peroxidase-like enzymatic activities by the photothermal effect, which lead the reactive oxygen species (ROS) generation to induce endoplasmic reticulum (ER) stress amplification, resulting the exposure of calreticulin (CALR) for providing the endogenous “eat-me” signals to macrophages. In a 4T1 breast cancer model, even under mild photothermal condition, MCC nanozymes effectively inhibit tumor growth and metastasis. Collectively, this dual-regulatory strategy presents a promising approach for macrophage-mediated cancer immunotherapy.