Amplification of Endoplasmic Reticulum Stress via Inhibiting Lipid Droplet Formation to Enhance Chemodynamic Immunotherapy

ABSTRACT Chemodynamic generation of hydroxyl radicals (•OH) from endogenous hydrogen peroxide (H ₂ O ₂ ) in the endoplasmic reticulum (ER) is promising to initiate cancer immunotherapy via ER stress‐mediated immunogenic cell death (ICD). However, the sprout of lipid droplets (LDs) is elevated under ER stress, which may limit chemodynamic immunotherapy due to the ability of LDs to reduce the production of ER stress‐inducing 4‑hydroxynonenal (4‐HNE, a lipid peroxidation (LPO) byproduct) by sequestering polyunsaturated fatty acids (PUFAs) and to block “eat‐me” signals by recruiting calreticulin (CRT). Here, an ER‐targeted chemodynamic nanoagent (denoted as TCBQ/iLD‐ER NPs) is reported for LDs downregulation‐enhanced chemodynamic immunotherapy. After uptake by tumor cells, TCBQ/iLD‐ER NPs comprising •OH‐generating tetrachloro‐1,4‐benzoquinone (TCBQ) and A‐922500 (an LDs formation inhibitor, defined as iLD) preferentially accumulate in the ER, where TCBQ reacts with high levels of ER H ₂ O ₂ to yield •OH accompanied by iLD release. •OH‐triggered LPO of PUFAs not only causes cancer cell death, but also produces 4‐HNE to provoke ER stress‐mediated ICD. Intriguingly, iLD inhibits LDs formation and thereby reduces the sequestration of PUFAs as well as the recruitment of CRT by LDs, enabling improved chemodynamic immunotherapeutic efficacy. This study highlights a versatile strategy to enhance chemodynamic immunotherapy by modulating intracellular LDs.