Spatiotemporal Cascade Targeting from the Cell Membrane to the Endoplasmic Reticulum for Chemoimmunotherapy via the Cyclometalated Iridium-Fatty Acid Scaffold

Lipids are fundamental components of membranous organelles, such as the plasma membrane and endoplasmic reticulum (ER), and targeting lipid metabolic reprogramming holds great promise for achieving efficient cancer immunotherapy. However, spatiotemporally cascaded targeting from the plasma membrane to the ER to rewire lipid metabolism and trigger antitumor immune responses remains unreported. Here, we systematically conjugated the antitumor metallodrug precursor Ir-NH2 to fatty acids that differ in chain length and degree of unsaturation. This screen identified Ir-OA─an oleic acid conjugate─as a spatiotemporally cascaded agent that targets sequentially from the plasma membrane to the ER. The lipophilic OA, composed of 18 carbon atoms and a C═C double bond, endows Ir-OA with moderately prolonged membrane anchoring ability, while the cyclometalated iridium scaffold empowers Ir-OA with enhanced membrane permeability and further induces membrane impairment. As incubation proceeds, Ir-OA progressively translocates to the ER, where it provokes ER stress and further rewires lipid metabolism, with a pronounced suppression of arachidonic acid (AA) metabolism. Notably, AA metabolism inhibition reciprocally reinforced ER stress, establishing a feed-forward loop that is synergistically reshaping the tumor microenvironment and ultimately awakening systemic antitumor immunity as well as achieving effective eradication of distant metastasis progression tumors in vivo. This work not only provides a potent antitumor immune amplifier by cascade targeting of membranous organelles but also demonstrates the validity of targeting the metabolic heterogeneity in cancer for cancer immunotherapy.