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Ovarian cancer remains the most lethal gynaecological malignancy, with tumour recurrence and chemoresistance posing significant therapeutic challenges. Emerging evidence suggests that cancer stem cells (CSCs), a rare subpopulation within tumours with self‐renewal and differentiation capacities, contribute to these hurdles. Therefore, elucidating the mechanisms that sustain CSCs is critical for improving treatment strategies. Mitophagy, a selective process for eliminating damaged mitochondria, plays a key role in maintaining cellular homeostasis, including CSC survival. Our study demonstrates that ovarian CSCs exhibit enhanced mitophagy, accompanied by elevated expression of the mitochondrial outer membrane receptors BNIP3 and BNIP3L. Knockdown of BNIP3 or BNIP3L significantly reduces mitophagy and impairs CSC self‐renewal, indicating that receptor‐mediated mitophagy is essential for CSC maintenance. Mechanistically, we identify that hyperactivated NF‐κB signalling drives the upregulation of BNIP3 and BNIP3L in ovarian CSCs. Inhibition of NF‐κB signalling, either via p65 knockdown or pharmacological inhibitors, effectively suppresses mitophagy. Furthermore, we demonstrate that elevated DNA‐PK expression contributes to the constitutive activation of NF‐κB signalling, thereby promoting mitophagy in ovarian CSCs. In summary, our findings establish that BNIP3/BNIP3L‐mediated mitophagy, driven by DNA‐PK‐dependent NF‐κB hyperactivation, is essential for CSC maintenance. Targeting the DNA‐PK/NF‐κB/BNIP3L‐BNIP3 axis to disrupt mitochondrial quality control in CSCs represents a promising therapeutic strategy to prevent ovarian cancer recurrence and metastasis.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by the lack of ER, PR, and HER2 expression. Its aggressive behavior, high degree of tumor heterogeneity, and immunosuppressive tumor microenvironment (TME) are associated with poor clinical outcomes, rapid disease progression, and limited therapeutic options. Although chimeric antigen receptor (CAR)-engineered T cell therapy has shown certain promise, its applicability in TNBC is hindered by antigen escape, TME-mediated suppression, and the logistical constraints of autologous cell production. In this study, we employed hematopoietic stem and progenitor cell (HSPC) gene engineering and a feeder-free HSPC differentiation culture to generate allogeneic IL-15-enhanced, mesothelin-specific CAR-engineered invariant natural killer T ( Allo15 MCAR-NKT) cells. These cells demonstrated robust and multifaceted antitumor activity against TNBC, mediated by CAR- and NK receptor-dependent cytotoxicity, as well as selective targeting of CD1d + TME immunosuppressive cells through their TCR. In both orthotopic and metastatic TNBC xenograft models, Allo15 MCAR-NKT cells demonstrated potent antitumor activity, associated with robust effector and cytotoxic phenotypes, low exhaustion, and a favorable safety profile without inducing graft-versus-host disease. Together, these results support Allo15 MCAR-NKT cells as a next-generation, off-the-shelf immunotherapy with strong therapeutic potential for TNBC, particularly in the context of metastasis, immune evasion, and treatment resistance. The online version contains supplementary material available at 10.1186/s13045-025-01736-9.