16-Hour Fasting Plus Serplulimab and CAPEOX as Neoadjuvant Therapy in pMMR/MSS Advanced Mid-to-Low Rectal Cancer

Although standard neoadjuvant chemoradiotherapy (nCRT) for locally advanced rectal cancer (LARC) effectively reduces local recurrence, radiotherapy-related toxicities and surgical complications severely impair patients' quality of life, making a radiotherapy-free strategy urgently needed. However, chemotherapy alone yields a pathological complete response (pCR) rate of only 6.6%-15%, which is far from satisfactory. The pMMR/MSS subtype, accounting for 90% of rectal cancers, is "immune-cold" and shows almost no response to PD-1 monotherapy; nonetheless, chemotherapy can reshape the tumor immune microenvironment, and multiple studies have demonstrated that combining chemotherapy with PD-1 inhibitors (without radiotherapy) can elevate pCR rates to 26.8%-42.9%, yet further improvement remains desirable. A recent mechanistic study published in Cell Metabolism (2026) revealed that a single 16-hour fasting episode before treatment promotes isoleucine accumulation in the tumor microenvironment, which enhances CD8+T-cell cytotoxic function and reduces exhaustion through acetyl-CoA metabolism and epigenetic reprogramming, thereby significantly sensitizing PD-1 inhibitors-and this intervention is non-invasive, low-cost, and easily adoptable by patients. Based on the above evidence, we hypothesize that the neoadjuvant triple-combination regimen of "16-hour fasting + chemotherapy + PD-1 inhibitor" (radiotherapy-free) in pMMR/MSS locally advanced mid-to-low rectal cancer may further increase pCR rates and tumor regression, offering a novel, highly effective, and low-toxicity therapeutic option for LARC patients.

Inclusion Criteria: 1. Willing and able to provide written informed consent. 2. Male or female subjects ≧ 18 years ≦ 75 of age. 3. Histological or cytological documentation of adenocarcinoma of the rectum. 4. No previous any systemic anticancer therapy for rectal cancer disease. 5. The primary rectal tumor is assessed as likely to be R0 resectable by a multidisciplinary colorectal cancer collaborative team, comprising at least 2 gastrointestinal surgeons and 1 radiologist. 6. The lower margin of the tumor is less than 10cm from the anus verge. 7. cT2N1-2M0, cT3N0-2M0, cT4N0-1M0 MSS with MRF(-) assessed by MRI. 8. Primary tumor can be detected by CT or MRI. 9. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 10. Eligible tumor tissues were identified for MSI/MMR assays. 11. Hepatitis B Surface Antigen (HBsAg) (-). 12. If HBsAg (+) , HBV-DNA must be less than 2500 copies/mL or 500 IU/mL to be enrolled. 13. Patients with HCV antibody (-) or HCV-RNA negative can be enrolled. Aspartate aminotransferase (AST) must be ≤ 3 x ULN for the lab. If HCV-RNA is positive, patients with both alanine aminotransferase (ALT) and aspartate aminotransferase (AST) performed ≤3×ULN could be enrolled. Patients infected with both hepatitis B virus and hepatitis C virus should be excluded (positive for HBsAg or HBcAb and positive for HCV antibodies). Exclusion Criteria: 1. Patients with recurrent rectal cancer or a history of pelvic radiotherapy. 2. Patients with a history of inflammatory bowel disease. 3. Patients with acquired immunodeficiency syndrome (AIDS-related illnesses) or known human immunodeficiency virus (HIV) disease (HIV1 antibody, HIV2 antibody, HTLV1 antibody positive) should be excluded. 4. Patients who are preparing for or have previously received an organ or bone marrow transplant. 5. History of myocardial infarction, poorly controlled arrhythmias (including QTc interval ≥470 ms in women) in the 6 months prior to enrollment (QTc interval calculated by Fridericia formula). 6. According to New York College of Cardiology (NYHA) standards for Grade III-IV cardiac insufficiency or cardiac color ultrasound: left ventricular ejection fraction (LVEF) \