Abstract 6602: Venetoclax enhances radiation-induced anticancer immunity in breast cancer.

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Abstract Estrogen receptor-positive (ER+) breast cancer (BC) lesions are poorly infiltrated by lymphocytes (immunologically "cold") and are therefore insensitive to immune checkpoint inhibitors (ICIs). Radiation therapy (RT) represents a clinically promising partner for ICIs, as RT converts immunologically "cold" ER+ BC into "hot" lesions, reflecting the ability of RT to elicit BAX/BAK-initiated mitochondrial permeabilization (MOMP) in cancer cells, culminating with cytosolic mtDNA accumulation, CGAS/STING signaling and type I IFN secretion, which supports anticancer immunity. We hypothesized type I IFN signaling could be further enhanced by exacerbating mitochondrial damages with Venetoclax, the FDA-approved BCL2 inhibitor. In vitro, Venetoclax treatment in mouse models of ER+ BC amplified RT-induced mtDNA release, increased RT-driven type I IFN production, and upregulated interferon-stimulated gene (ISG) expression. Type I IFN signaling was abrogated by the pharmacologic inhibition of CGAS or STING, as well as in STING-deficient cells or in mtDNA-depleted (Rho0) cells, confirming that Venetoclax enhances RT-driven type I IFN production via the CGAS/STING pathway. In vivo, Venetoclax significantly improved RT-mediated tumor control, an effect that was further enhanced by CTLA4 blockage. However, RT also triggered the removal of damaged mitochondria in a dose- and time-dependent manner. This process was suppressed by genetic deletion of the essential autophagy genes Atg5 or Atg7. Moreover, RT-induced mitophagy depended on BAX/BAK-mediated MOMP, as Venetoclax further enhanced RT-induced mitophagy, whereas BAX/BAK-deficient cells failed to activate mitophagy in response to RT and were unresponsive to Venetoclax. By investigating the mechanistic link between mitophagy (which degrades permeabilized, mtDNA-releasing mitochondria) and mtDNA-dependent type I IFN production, we observed that 1) blocking mitophagy with Atg5-/- cells increased cytosolic mtDNA accumulation and type I IFN production whereas 2) activating mitophagy with Urolithin A reduced cytosolic mtDNA accumulation and type I IFN production. These findings strongly suggest that mitophagy modulates type I IFN signaling. In summary, RT-driven BAX/BAK-dependent MOMP mediates both mtDNA release, which activates type I IFN signaling and enhances anticancer immunity, but also mitophagy, which limits type I IFN signaling and may therefore constrain anticancer immunity. To maximize MOMP-dependent type I IFN production, it is crucial to uncouple these mechanisms. Collectively, our findings identify both BCL2 and mitophagy as immune checkpoints that suppress RT-induced immune responses. These pathways represent actionable targets for novel therapeutic strategies to overcome immunotherapy resistance not only in ER+ breast cancer, but also in other "cold" tumor types. Citation Format: Emma Guilbaud, Ai Sato, Lorenzo Galluzzi.. Venetoclax enhances radiation-induced anticancer immunity in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6602.

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