In tumor-bearing mice, cyclic fasting or fasting-mimicking diets (FMD) enhance the activity of antineoplastic treatments by modulating systemic metabolism and boosting antitumor immunity. Here we conducted a clinical trial to investigate the safety and biological effects of cyclic, five-day FMD in combination with standard antitumor therapies. In 101 patients, the FMD was safe, feasible, and resulted in a consistent decrease of blood glucose and growth factor concentration, thus recapitulating metabolic changes that mediate fasting/FMD anticancer effects in preclinical experiments. Integrated transcriptomic and deep-phenotyping analyses revealed that FMD profoundly reshapes anticancer immunity by inducing the contraction of peripheral blood immunosuppressive myeloid and regulatory T-cell compartments, paralleled by enhanced intratumor Th1/cytotoxic responses and an enrichment of IFNγ and other immune signatures associated with better clinical outcomes in patients with cancer. Our findings lay the foundations for phase II/III clinical trials aimed at investigating FMD antitumor efficacy in combination with standard antineoplastic treatments. Significance: Cyclic FMD is well tolerated and causes remarkable systemic metabolic changes in patients with different tumor types and treated with concomitant antitumor therapies. In addition, the FMD reshapes systemic and intratumor immunity, finally activating several antitumor immune programs. Phase II/III clinical trials are needed to investigate FMD antitumor activity/efficacy. This article is highlighted in the In This Issue feature, p. 1

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Objective: To ascertain, in cN0/1 breast cancer patients given primary chemotherapy followed by sentinel node biopsy (SNB), whether SNB alone is adequate axillary treatment if the sentinel nodes (SNs) are clear (pN0). Summary Background Data: 2020 guidelines do not recommend SNB in most cN1 patients with clear SNs after primary chemotherapy because the high SNB false negative rate might lead to poorer outcomes. Methods: We prospectively assigned SNB after primary chemotherapy to 353 consecutive cT2 cN0/1 patients, median age 47 years (range 22-76) treated from 2007 to 2015. If the SNs were pN0, patients generally received no further axillary treatment (SNB only); if the SNs were pN1, completion axillary dissection (AD) (SNB + AD) was usually performed. Primary outcomes were overall (OS) and disease-free (DFS) survival in SNB only versus SNB + AD patients, assessed by Kaplan-Meier and compared using log-rank test, with use of propensity scores to account for bias due to nonrandom assignment to SNB versus SNB + AD. Results: Median follow-up was 108 months, interquartile range 66 to 136. OS and DFS did not differ significantly between the groups by propensity score- weighted comparison: 10-year OS 89% [95% confidence interval (CI): 81%- 99%] in SNB only patients versus 86% (95%CI: 78%–95%) in SNB + AD patients; 10-year DFS 79% (95%CI: 68%–92%) versus 69% (95%CI: 58%–81%). No SNB-only patient developed axillary failure. Conclusions: cT2 cN0/1 patients whose SNs are disease-free (pN0) after primary chemotherapy can be offered SNB (with no further axillary treatment if the SNs are negative), irrespective of axillary status beforehand, without affecting OS or DFS.