The pentose phosphate pathway in immunotherapy

Emerging evidence has highlighted the influence of cellular metabolism on both cancer and T cell growth and survival, including in the context of adoptive cell immunotherapy. It is known that T cells heavily rely on glycolysis for cell proliferation and mediating effector functions. However, less is known about the role of the pentose phosphate pathway (PPP), a parallel metabolic pathway that produces antioxidant and biosynthetic precursors, toward regulating antitumor T cell function. In this review, we summarize the PPP's role as a time-dependent regulator of T cell activation and redox balance, and its association with improved functional capacity in exhausted T cells. We further highlight the contrasting role of the PPP for CD8+ and CD4+ T cell differentiation in guiding antitumor responses, as well as a unique connection in the glycogen-PPP axis to CD8+ memory T cells. Finally, we summarize global metabolic regulators that drive expression of PPP enzymes and discuss future avenues for immunotherapy that could take advantage of our current understanding of the PPP's role in T cell metabolism.