Caspase‐8: A key protein of cross‐talk signal way in “PANoptosis” in cancer

Abstract Cysteinyl aspartate specific proteinase (Caspase)‐8 has long been considered a promoter of apoptosis and part of the mechanism by which cytotoxic drugs kill cancer cells. With the continuous exploration of the types of programmed cell death, an increasing number of studies have confirmed that caspase‐8 plays an important role in cancer. Recently, scholars have proposed the term “PANoptosis,” which mainly includes three programmed cell death modes, namely pyroptosis, apoptosis and necroptosis. In addition to mediating endogenous apoptotic pathways, caspase‐8 can also participate in the cleavage of gasdermin (GSDM) family proteins to induce pyroptosis. Furthermore, the expression of enzymatically inactive caspase‐8 (C362S) can cause embryonic lethality and inflammatory tissue destruction in mice by inducing necroptosis and pyroptosis. Therefore, the activation and deletion of caspase‐8 enzyme activity, as well as the knockout of the coding gene, are closely related to “PANoptosis.” In addition, caspase‐8 can also improve the tumor microenvironment and enhance tumor antiimmunity. Studies have shown that caspase‐8 is also associated with tumor growth and invasion, angiogenesis and metastasis, therapeutic resistance and poor clinical outcomes. Therefore, it is very important to measure the cancer‐promoting and anticancer effects of caspase‐8 and find a balance, and to study its role in the effect of “PANoptosis” in depth. This article reviews the role of caspase‐8 in “PANoptosis” in cancer to provide new strategies and targets for cancer.