Triaptosis—an emerging paradigm in cancer therapeutics

Cancer remains one of the most critical global public health challenges, exerting profound social, economic, and clinical burdens while limiting gains in human life expectancy. Despite advances in surgery, radiotherapy, chemotherapy, targeted therapy, and immunotherapy, treatment failure and cancer recurrence are frequently driven by a subset of resistant tumor cells that evade conventional programmed cell death pathways. The scientific community has thus been actively exploring strategies to engage alternative intracellular “death switches” within malignant cells. In recent years, the discovery of novel immunogenic cell death modalities—such as pyroptosis, ferroptosis, and cuproptosis—has reinvigorated anticancer efforts. These mechanisms can remodel the tumor microenvironment, effectively converting immunologically “cold” tumors into “hot” ones, thereby augmenting the efficacy of immunotherapy.

In a groundbreaking 2024 study published in Science, a new form of cell death, termed triaptosis, was first reported. The study revealed that menadione, a common precursor of vitamin K, acts as a potent pro-oxidant that selectively oxidizes a key kinase, PIK3C3/VPS34. This oxidation disrupts endosomal function, impairing cargo sorting and transport, and ultimately leads to the accumulation of massive intracellular vacuoles, culminating in plasma membrane rupture and cell death. This process is mechanistically distinct from all previously known cell death pathways. In a mouse model of prostate cancer, oral administration of menadione to induce triaptosis resulted in superior tumor control compared to standard clinical regimens, with a favorable safety profile, highlighting its promising translational potential.

In this context, the research team led by Associate Professor Lin-Lin Bu from Wuhan University School and Hospital of Stomatology, has published a comprehensive review entitled “Triaptosis and Cancer: Next Hope?” in the journal Research. This article systematically elaborates the triaptosis pathway from molecular mechanism to therapeutic application, detailing its signaling cascade, discussing the central role of oxidative stress homeostasis in cancer, and offering a forward-looking perspective on future directions—collectively underscoring the compelling potential of triaptosis as a novel anticancer strategy.

The mechanism of triaptosis targets a vulnerability inherent in many cancer cells. To sustain rapid proliferation, cancer cells often exhibit a heightened dependence on their endomembrane trafficking system. By specifically disrupting endosomal function, triaptosis may precisely strike this “Achilles' heel.” Moreover, triaptosis holds considerable promise for combination with immunotherapy. Although its immunogenic potential remains unverified, endosomes play an indispensable role in antigen presentation and immune cell activation. Therefore, inducing triaptosis may not only kill tumor cells but also stimulate a specific antitumor immune response, potentially synergizing with immune checkpoint inhibitors to effectively convert “cold” tumors into “hot” ones. Furthermore, since triaptosis operates independently of canonical apoptotic pathways, it may offer a final-line therapeutic option for patients resistant to existing treatments.

The review also outlines future research directions concerning the mechanism and targeting of triaptosis (Fig. 1). Subsequent studies will focus on identifying and developing novel agents that can efficiently and selectively induce triaptosis. To maximize efficacy and minimize side effects, intelligent drug delivery systems capable of precise tumor targeting should be engineered. In addition, elucidating the crosstalk between triaptosis and other cell death modalities may inform the design of sophisticated combination therapies and offer new avenues to overcome treatment resistance. It is worth noting that preliminary evidence suggests menadione also shows efficacy in a non-cancer disease, indicating that the implications of triaptosis may extend well beyond oncology.

The discovery of triaptosis not only expands our understanding of fundamental biological processes governing cell death but also represents a promising strategy in the fight against cancer. It is our hope that triaptosis-based therapeutic innovations will soon bridge the gap between bench and bedside, offering renewed hope for cancer patients as the “next hope” in oncology.

Sources: https://spj.science.org/doi/10.34133/research.0880

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