Chimeric antigen receptor cells as a tool for localized delivery of TNFα in solid cancer treatment

Chimeric antigen receptor (CAR)-T cells are effective in treating blood cancers but not solid cancers and can cause severe side effects, including cytokine release syndrome (CRS). One strategy to enhance the efficacy of CAR-T cells while avoiding CRS in cancer treatment is to deliver a single tumoricidal factor. TNFα is well known for triggering apoptosis signaling; however, it alone is not effective in treating cancers because it significantly increases the levels of inhibitor of apoptosis proteins (IAPs), a family of E3 ubiquitin ligases that block caspase-induced apoptosis. Thus, localized delivery of TNFα by targeting the tumors using the adoptive cells combined with an IAP antagonist, which degrades IAP proteins, could lead to improved outcomes in cancer treatment. This article reviews TNFα-induced apoptosis signaling pathway, outlines the principles for designing CAR-T cells, CAR-macrophages and CAR-dendritic cells expressing TNFα, used alone or in combination with IAP antagonists, and discusses the potential contraindications of IAP antagonists with several clinical used drugs for cancer treatment.