The PPTC7/BNIP3/NIX axis induces cGAS/STING-mediated senescence and augments CAR-T efficacy by repressing tumor-intrinsic mitophagy

In multiple myeloma (MM), resistance to B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor T-cell (CAR-T) treatment continues to limit therapeutic benefit, whereas the tumor-intrinsic factors governing sensitivity to CAR-T remain poorly understood. Here, integrating public single-cell RNA-seq data with transcriptomic profiling of MM cells before and after CAR-T exposure, we identified the mitochondrial protein PPTC7 as a key modulator linking tumor mitophagy to innate immune activation and CAR-T efficacy. Mechanistically, PPTC7 acted as a negative regulator of tumor-intrinsic mitophagy by promoting SCF^FBXL4-dependent ubiquitination and proteasomal degradation of the mitophagy receptors BNIP3 and NIX, thereby suppressing mitophagic flux. Consistent with this, PPTC7 overexpression inhibited mitophagy, caused mitochondrial dysfunction, and increased cytosolic leakage of mitochondrial DNA (mtDNA), whereas PPTC7 knockdown stabilized BNIP3/NIX, enhanced mitophagy, and reduced cytosolic mtDNA. The accumulated cytosolic mtDNA consequent to mitophagy suppression activated the cGAS/STING pathway, induced a senescence-associated secretory phenotype, and remodeled the inflammatory tumor microenvironment. Functionally, PPTC7-mediated mitophagy repression markedly enhanced CAR-T cytotoxicity in vitro and promoted CAR-T infiltration and tumor control in vivo. Rescue experiments further supported this axis: restoring mitophagy via NIX attenuated mtDNA leakage and dampened cGAS/STING signaling and CAR-T activity, whereas re-activating cGAS reinstated inflammatory signaling and CAR-T effector function. Collectively, our findings define a tumor-intrinsic PPTC7-BNIP3/NIX-mtDNA-cGAS/STING circuit in which suppression of mitophagy increases tumor immunogenicity and sensitizes MM to CAR-T therapy, highlighting PPTC7 as a potential immune-sensitizing target to overcome CAR-T resistance. Our findings reveal the mechanism by which PPTC7 regulates mitophagy, influencing CAR-T efficacy. We demonstrate that PPTC7 inhibits mitophagy in MM cells by promoting the ubiquitin-dependent degradation of BNIP3 and NIX. Our findings reveal that PPTC7 activates the cGAS/STING signaling pathway, thereby inducing senescence in MM cells and enhancing antitumor immunity. We show that inhibition of mitophagy via PPTC7 increases the sensitivity of MM cells to CAR-T treatment. This study provides novel molecular insights and a potential therapeutic target for enhancing CAR-T efficacy in MM, with promising clinical implications.