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Cancer immunology and immunotherapy are driving forces of research and development in oncology, mostly focusing on CD8 + T cells and the tumor microenvironment. Recent progress highlights the importance of CD4 + T cells, corresponding to the long-known fact that CD4 + T cells are central players and coordinators of innate and antigen-specific immune responses. Moreover, they have now been recognized as anti-tumor effector cells in their own right. Here we review the current status of CD4 + T cells in cancer, which hold great promise for improving knowledge and therapies in cancer., (© 2023. Springer Nature America, Inc.)

Most cancer cells have high need for nicotinamide adenine dinucleotide (NAD + ) to sustain their survival. This led to the development of inhibitors of nicotinamide (NAM) phosphoribosyltransferase (NAMPT), the rate-limiting NAD + biosynthesis enzyme from NAM. Such inhibitors kill cancer cells in preclinical studies but failed in clinical ones. To identify parameters that could negatively affect the therapeutic efficacy of NAMPT inhibitors and propose therapeutic strategies to circumvent such failure, we performed metabolomics analyses in tumor environment and explored the effect of the interaction between microbiota and cancer cells. Here we show that tumor environment enriched in vitamin B3 (NAM) or nicotinic acid (NA) significantly lowers the anti-tumor efficacy of APO866, a prototypic NAMPT inhibitor. Additionally, bacteria (from the gut, or in the medium) can convert NAM into NA and thus fuel an alternative NAD synthesis pathway through NA. This leads to the rescue from NAD depletion, prevents reactive oxygen species production, preserves mitochondrial integrity, blunts ATP depletion, and protects cancer cells from death.Our data in an in vivo preclinical model reveal that antibiotic therapy down-modulating gut microbiota can restore the anti-cancer efficacy of APO866. Alternatively, NAphosphoribosyltransferase inhibition may restore anti-cancer activity of NAMPT inhibitors in the presence of gut microbiota and of NAM in the diet., (© 2022. The Author(s).)