Abstract
<div>Abstract<p>As a safe, feasible, and inexpensive dietary intervention, fasting-mimicking diet (FMD) exhibits excellent antitumor efficacy by regulating metabolism and boosting antitumor immunity. A better understanding of the specific mechanisms underlying the immunoregulatory functions of FMD could help improve and expand the clinical application of FMD-mediated immunotherapeutic strategies. In this study, we aimed to elucidate the role of metabolic reprogramming induced by FMD in activation of antitumor immunity against colorectal cancer. Single-cell RNA sequencing analysis of intratumoral immune cells revealed that tumor-infiltrating IgA<sup>+</sup> B cells were significantly reduced by FMD treatment, leading to the activation of antitumor immunity and tumor regression in murine colorectal cancer models. Mechanistically, FMD delayed tumor growth by repressing B-cell class switching to IgA. Therefore, FMD-induced reduction of IgA<sup>+</sup> B cells overcame the suppression of CD8<sup>+</sup> T cells. The immunoregulatory and antitumor effects of FMD intervention were reversed by IgA<sup>+</sup> B-cell transfer. Moreover, FMD boosted fatty acid oxidation (FAO) to trigger RUNX3 acetylation, thus inactivating C<sub>α</sub> gene transcription and IgA class switching. IgA<sup>+</sup> B-cell expansion was also impeded in patients placed on FMD, while B-cell expression of carnitine palmitoyl transferase 1A (CPT1A), the rate-limiting enzyme of FAO, was increased. Furthermore, CPT1A expression was negatively correlated with both IgA<sup>+</sup> B cells and IgA secretion within colorectal cancer. Together, these results highlight that FMD holds great promise for treating colorectal cancer. Furthermore, the degree of IgA<sup>+</sup> B cell infiltration and FAO-associated metabolic status are potential biomarkers for evaluating FMD efficacy.</p>Significance:<p>Metabolic reprogramming of B cells induced by fasting-mimicking diet suppresses IgA class switching and production to activate antitumor immunity and inhibit tumor growth.</p><p><i><a href="https://aacrjournals.org/cancerres/article/doi/10.1158/0008-5472.CAN-23-2257" target="_blank">See related commentary by Bush and Perry, p. 3493</a></i></p></div>
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