Chen et al. designed an overnight 16h fasting regimen that augmented ICB efficacy in mice and patients with colorectal cancer. Fasting reprogrammed tumor cell nutrient preferences, triggering a metabolic trade-off that enriched intratumoral isoleucine (Ile). Ile fueled the acetyl-CoA pool in CD8+ T cells, which coordinated the epigenetic landscape and membrane lipid dynamics required for CD8+ T cell effector functions. Fasting reduced exhausted T cell populations, increased TEMRA and TRM effector functions, augmented the clonal expansion and cytotoxic activity of CD8+ T cells, and enhanced anti-PD-1 efficacy in preclinical models and patients with CRC.
Contributed by Shishir Pant
ABSTRACT: Dietary interventions hold promise for cancer therapy but often require prolonged, poorly tolerated regimens. Furthermore, how transient nutrient deprivation affects the metabolic interplay between tumor and immune cells within the tumor microenvironment (TME) remains unknown. Here, we introduce a brief, 16-h fasting regimen that enhances immunotherapy efficacy in both mice and humans. We found that this transient nutrient stress alters tumor-cell nutrient preferences, creating a metabolic window that can be leveraged to augment treatment. Mechanistically, short-term fasting induces intratumoral accumulation of isoleucine, which reconfigures CD8(+) T cell epigenetic programs and phospholipid remodeling, thereby licensing enhanced anti-tumor capacity. In patients receiving neoadjuvant immunotherapy, short-term fasting was able to enhance CD8(+) clonal expansion and cytotoxic programs. These findings establish a clinically feasible, well-tolerated dietary regimen that counters nutrient competition in the TME and that provides a tractable path to strengthen existing immunotherapy regimens.
Author Info: (1) Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University
Author Info: (1) Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310017, P.R. China; Cancer Center, Zhejiang University, Hangzhou 310058, P.R. China. (2) Institute of Immunology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China. (3) Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, P.R. China. (4) Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310017, P.R. China; Cancer Center, Zhejiang University, Hangzhou 310058, P.R. China. (5) Institute of Immunology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China. (6) Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310017, P.R. China; Cancer Center, Zhejiang University, Hangzhou 310058, P.R. China. (7) Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310017, P.R. China; Cancer Center, Zhejiang University, Hangzhou 310058, P.R. China. (8) Eye Center, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China. (9) Center for Regeneration and Aging Medicine, The Fourth Affiliated Hospital of School of Medicine, International School of Medicine, International Institutes of Medicine, Yiwu 322000, P.R. China. (10) Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310017, P.R. China; Cancer Center, Zhejiang University, Hangzhou 310058, P.R. China. (11) Cancer Center, Zhejiang University, Hangzhou 310058, P.R. China; Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China; Institute of Genetics, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China. (12) Institute of Immunology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China. (13) Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou 311113, P.R. China. (14) Institute of Immunology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China. (15) Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou 311113, P.R. China. (16) Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310017, P.R. China; Cancer Center, Zhejiang University, Hangzhou 310058, P.R. China. (17) Institute of Immunology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China. (18) Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310017, P.R. China; Cancer Center, Zhejiang University, Hangzhou 310058, P.R. China. (19) Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310017, P.R. China; Cancer Center, Zhejiang University, Hangzhou 310058, P.R. China. (20) Cancer Center, Zhejiang University, Hangzhou 310058, P.R. China; Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China; Institute of Genetics, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China. (21) Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310017, P.R. China; Cancer Center, Zhejiang University, Hangzhou 310058, P.R. China; Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou 310020, P.R. China; Zhejiang Provincial Clinical Research Center for CANCER, Hangzhou 310009, P.R. China. Electronic address: dingkefeng@zju.edu.cn. (22) Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310017, P.R. China; Institute of Immunology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou 311113, P.R. China; Zhejiang Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China. Electronic address: diwang@zju.edu.cn.
