Chirality‐Directed Strategy to Overcome Tumor Resistance to Cuproptosis and Enhance Cuproptosis‐Immunotherapy

Cuproptosis, a recently identified copper‐dependent metabolic cell death pathway, eliminates tumor cell via toxic aggregation of lipoylated enzymes in the tricarboxylic acid cycle. Paradoxically, as cuproptosis progresses, elevated intracellular copper level triggers adaptive metabolic reprogramming that enhances fatty acid β ‐oxidation (FAO), conferring resistance to cuproptosis. Here, a chirality‐directed copper‐based metabolic nanoregulator (Cu‐D‐Car@HA) was elaborately proposed for amplifying the therapeutic outcome of combined therapy with cuproptosis and immunotherapy by overcoming this adaptive resistance. Specifically, Cu‐D‐Car@HA was designed to selectively disassemble in the acidic environment in tumor cells, releasing Cu + /Cu 2+ and D‐carnitine (D‐Car), respectively. Intracellular Cu 2+ would be reduced to Cu + to induce cuproptosis, while the free D‐Car competitively occupies the L‐carnitine (L‐Car) binding site of carnitine palmitoyltransferase‐I, thereby inhibiting the upregulated FAO to overcome tumor resistance to cuproptosis. Beyond potentiating cuproptosis, Cu‐D‐Car@HA nanoregulator could markedly induce immunogenic cell death and downregulate membrane PD‐L1 expression by disturbing the acetyl‐CoA‐dependent PD‐L1 acetylation. Strikingly, the combination of Cu‐D‐Car@HA and anti‐PD‐1 antibody treatment not only drove regression of established tumors but also markedly inhibited tumor metastasis. This chirality‐directed strategy developed a promising paradigm to overcome tumor resistance to cuproptosis and collaboratively enhance cuproptosis‐immunotherapy.