Neoadjuvant Chemoradiotherapy Plus PD-1 Blockade ± CTLA-4 Blockade for High-Risk Locally Advanced Rectal Cancer (pMMR/MSS): A National Multicenter, Prospective, Randomized Controlled Trial

• 1: Signed written informed consent and voluntary participation in this study

  2: Aged 18-75 years, male or female

  3: Rectal adenocarcinoma confirmed by histopathology, with immunohistochemistry results indicating pMMR or genetic testing results indicating MSS

  4: High-risk locally advanced rectal cancer assessed by MRI, without distant metastasis, and meeting at least one of the following: T4Nany, TanyN2, MRF+, lateral lymph node+, EMVI+; no tumor deposits, or no high-risk factors for local recurrence as judged by the investigator

  5: The lower edge of the tumor is ≤10 cm from the anal verge

  6: Surgically resectable

  7: Able to swallow tablets normally

  8: ECOG PS 0-1

  9: No prior antitumor treatment for rectal cancer, including radiotherapy, chemotherapy, surgery, etc.

  10: Planned to undergo surgery after completion of neoadjuvant therapy

  11: No contraindications to surgery

  12: Normal function of major organs

Exclusion Criteria:

• 1: History of allergy to monoclonal antibodies, sintilimab, ipilimumab N01, oxaliplatin, capecitabine, or any other excipients

  2: Previously received or currently receiving any of the following treatments: a) Any surgery, radiotherapy, chemotherapy, targeted therapy, immunotherapy, etc. for the tumor; b) Within 2 weeks before the first use of the study drug, currently using immunosuppressive drugs or systemic hormone therapy for the purpose of immunosuppression (dose > 10 mg/day prednisone or equivalent); in the absence of active autoimmune disease, inhaled or topical steroids and adrenal corticosteroid replacement at a dose > 10 mg/day prednisone or equivalent are permitted; c) Received a live attenuated vaccine within 4 weeks before the first use of the study drug; d) Underwent major surgery or had severe trauma within 4 weeks before the first use of the study drug

  3: Has any active autoimmune disease or a history of autoimmune disease, including but not limited to: interstitial pneumonia, enteritis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism (may be considered for enrollment after hormone replacement therapy); patients with psoriasis or childhood asthma/allergy that has completely resolved and requires no intervention in adulthood may be considered for enrollment, but patients who require medical intervention with bronchodilators must not be enrolled

  4: History of immunodeficiency, including positive HIV test, or other acquired or congenital immunodeficiency diseases, or history of organ transplantation or allogeneic bone marrow transplantation

  5: Presence of poorly controlled cardiac clinical symptoms or diseases, including but not limited to: (1) heart failure of NYHA class II or above, (2) unstable angina, (3) myocardial infarction within 1 year, (4) clinically significant supraventricular or ventricular arrhythmias without clinical intervention or still poorly controlled after clinical intervention

  6: Severe infection (CTCAE > grade 2) within 4 weeks before the first use of the study drug, such as severe pneumonia, bacteremia, infectious complications, etc. requiring hospitalization; baseline chest imaging suggesting active pulmonary inflammation, presence of symptoms and signs of infection within 14 days before the first use of the study drug, or need for oral or intravenous antibiotic treatment, except for prophylactic antibiotic use; active pulmonary tuberculosis infection found by medical history or CT examination, or history of active pulmonary tuberculosis infection within 1 year before enrollment, or history of active pulmonary tuberculosis infection more than 1 year ago but without regular treatment

  7: Presence of active hepatitis B (HBV DNA ≥ 2000 IU/mL or 10\^4 copies/mL), hepatitis C (positive hepatitis C antibody and HCV RNA above the lower limit of detection of the assay method)

  8: Diagnosed with other malignant tumors within 5 years before the first use of the study drug, unless the malignant tumor has a low risk of metastasis or death (5-year survival rate > 90%), such as adequately treated basal cell carcinoma or squamous cell skin cancer or carcinoma in situ of the cervix, etc., may be considered for enrollment

  9: Pregnant or breastfeeding women

  10: As judged by the investigator, presence of other factors that may lead to forced early termination of the study, such as other serious diseases (including mental illness) requiring concomitant treatment, alcoholism, drug abuse, family or social factors, or factors that may affect subject safety or compliance