A Mitochondrion‐Targeted NIR‐II Modulator for Synergistic Ferroptosis–Immunotherapy

Abstract Immune checkpoint inhibitors (ICIs) have limited clinical efficacy against gastric cancer (GC) due to the nonimmunogenic tumor microenvironment. Therefore, inducing immunogenic cell death (ICD) to reprogram the immunogenic landscape is essential. This study develops HD‐FA nanoparticles by encapsulating a novel mitochondrion‐targeted NIR‐II modulator, HD, within DSPE‐PEG‐FA. HD‐FA exhibits superior spatiotemporal resolution, robust tumor accumulation, and minimal adverse effects. Upon 808 nm laser irradiation, HD‐FA generates reactive oxygen species, leading to ferroptosis and oxidative stress damage in GC cells by inhibiting the SLC7A11/GSH/GPX4 axis. HD‐FA triggers ICD, resulting in antitumor activity not only in primary tumors but also in distant tumors. Moreover, HD‐FA promotes dendritic cell maturation, increases the effector‐memory T‐cell frequency, and reduces the presence of myeloid‐derived suppressor cells, thereby fostering enhanced antitumor immunity. This study presents the first report of a novel NIR‐II modulator for GC immunogenic synergistic therapy with ICIs, marking significant advancements in the fight against GC.