Newly Described Cell Death Pathway May Provide Therapeutic Opportunity

Although inflammation and deregulated cellular metabolism are independent hallmarks of cancer, there is also crosstalk between the two, whereby metabolic disruption exacerbates inflammation and inflammatory cell death. However, the mechanisms by which these pathways may cooperate to drive cell death remain elusive. Wang and colleagues set out to address this by establishing and characterizing in vitro and in vivo innate immunity activation and metabolic disruption (IIAMD) models. Importantly, fasted mice treated with the proinflammatory stimulus lipopolysaccharide (LPS) exhibited increased mortality and tissue damage when compared with the control arm (LPS alone). A similar cooperative effect was observed in vitro, as the combination of LPS or other innate immune triggers (e.g. TLR ligands or TNF) with carbon starvation (CS) enhanced cell death in murine bone marrow–derived macrophages, as well as cancer cells. Preliminary assessments revealed that inhibition of well-characterized cell death pathways, including apoptosis, pyroptosis, necroptosis, PANoptosis, and ferroptosis, was insufficient to reverse the IIAMD-induced phenotype, suggesting a previously uncharacterized mechanism. Metabolomic screening of LPS plus CS–treated cells indicated that this combination of stressors markedly reduced levels of the antioxidant glutathione. Follow-up live cell imaging revealed that IIAMD cells consequently harbored prolonged oxidative stress prior to cell death, localized to distinct puncta at the periphery of the cells. Further spatiotemporal analyses revealed that IIAMD leads to the prolonged localization of mitochondria undergoing BAX/BAK1/BID-dependent oxidative stress at the plasma membrane, a process termed mitoxyperiosis, eventually leading to the breakdown of membrane integrity (mitoxyperilysis). Results from a chemical compound screen and RNA sequencing suggested that mitoxyperilytic cell death may be regulated by mTOR signaling. Further in vitro analyses supported this notion, whereby mTOR inhibition with Torin-1 reduced cell death elicited by IIAMD. Interestingly, mTOR inhibition did not affect IIAMD-induced cell death by mediating oxidative stress, but rather by changing the structural dynamics of mitochondria-membrane interactions. Treatment of IIAMD cells with Torin-1 restored lamellipodia formation at the plasma membrane and limited its contact with damaged mitochondria. In a syngeneic B16 melanoma model, the combination of fasting and intratumoral LPS treatment to induce mitoxyperilysis reduced tumor volume and increased necrosis in an mTOR-dependent manner, highlighting the antitumor potential of IIAMD. Taken together, these results suggest that inflammation and metabolic dysfunction cooperatively promote mitoxyperilysis that can regress tumors, highlighting promising translational applications for this newly described cell death pathway.Wang Y, Lu J, Carisey AF, Chadchan SB, Lee HW, Malireddi RKS, et al. Innate immune and metabolic signals induce mitochondria-dependent membrane lysis via mitoxyperiosis. Cell 2025;188:7155–74.Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.