Modified Long-Course Radiotherapy Followed by Chemotherapy and PD-1 Inhibitor for MSS/pMMR High-risk Mid/Low LARC (MODIFI-RC-I)

Inclusion Criteria:

• Voluntarily signs a written informed consent form.

• Aged between 18 and 75 years at enrollment.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

• Expected survival of more than 2 years.

• Histologically confirmed rectal adenocarcinoma.

• Tumor biopsy immunohistochemistry indicating pMMR (MSH1, MSH2, MSH6, and PMS2 allpositive) or genetic testing confirming MSS.

• According to the 8th edition of the AJCC TNM classification, high-resolution MRI ±endorectal ultrasound confirms clinical staging as cT3-4NanyM0 or cTxN+M0 (stageII-III rectal cancer). MRI confirms the tumor is located below the peritonealreflection without lateral lymph node metastasis.

• Before study enrollment, a responsible surgical attending physician must evaluatethe patient's medical history to confirm eligibility for R0 resection with curativeintent.

• No prior systemic or local anti-tumor treatment for rectal cancer, includingradiotherapy, chemotherapy, immunotherapy, biologics, or small-molecule targetedtherapy.

• Willing to provide tumor tissue and peripheral blood samples for research purposesduring screening and throughout the study.

• Adequate organ function:

• Hematology (without recent blood transfusions or growth factor support within 7 daysbefore treatment):

• Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L (1,500/mm³)

• Platelet count ≥ 100 × 10⁹/L (100,000/mm³)

• Hemoglobin ≥ 90 g/L

• Renal function:

• Estimated creatinine clearance (CrCl) ≥ 50 mL/min (calculated using theCockcroft-Gault formula)

• Urine protein < 2+ or 24-hour urine protein quantification < 1.0 g

• Liver function:

• Total bilirubin (TBil) ≤ 1.5 × upper limit of normal (ULN)

• AST and ALT ≤ 2.5 × ULN

• Serum albumin (ALB) ≥ 28 g/L

• Coagulation function: o INR and APTT ≤ 1.5 × ULN

• Cardiac function: o Left ventricular ejection fraction (LVEF) ≥ 50%

• Female participants of childbearing potential must have a negative urine or serumpregnancy test within 3 days before starting study treatment. If a urine pregnancytest result is unclear, a confirmatory serum pregnancy test must be conducted.Participants with childbearing potential who engage in sexual activity withnon-sterilized male partners must use highly effective contraception from screeninguntil 120 days after the last dose of study treatment. The use of periodicabstinence and fertility awareness methods is not considered acceptablecontraception.

• Definition of females of childbearing potential (FCBP): Women who have not undergonesurgical sterilization (bilateral tubal ligation, bilateral oophorectomy, or totalhysterectomy) or who have not been naturally postmenopausal for at least 12consecutive months (confirmed by FSH levels within the postmenopausal range).

• Highly effective contraception methods: Must have a failure rate of <1% per yearwhen used consistently and correctly. In addition to barrier methods, FCBP must usean additional hormonal contraceptive method (e.g., oral contraceptives).

• Participants must be willing and able to comply with study visit schedules,treatment plans, laboratory tests, and other study-related requirements.

Exclusion Criteria:

• Presence of suspected metastatic lesions or locally advanced unresectable disease,regardless of disease stage.

• Diagnosis of other malignancies within the past five years, except for patients withmalignancies cured through local treatment (e.g., basal or squamous cell skincancer, superficial bladder cancer, ductal carcinoma in situ of the breast).

• Concurrent enrollment in another clinical study, unless it is an observational,non-interventional study or a follow-up phase of an interventional study.

• Presence of intestinal obstruction, perforation, or bleeding requiring emergencysurgery.

• Multiple primary rectal cancers.

• History of pelvic or abdominal radiotherapy.

• Inability to swallow tablets, malabsorption syndrome, or any condition affectinggastrointestinal absorption.

• Prior systemic or local anti-tumor treatment for locally advanced rectal cancer,including radical surgery, chemotherapy, radiotherapy, immunotherapy (e.g., immunecheckpoint inhibitors, immune cell therapy), biological agents, or targeted therapy.

• Use of nonspecific immunomodulatory treatment (e.g., interleukins, interferons,thymosin, TNF) within two weeks before study treatment (excluding IL-11 forthrombocytopenia); use of traditional Chinese medicine with anti-tumor indicationswithin one week before study treatment.

• Active autoimmune disease requiring systemic treatment in the past two years, exceptfor replacement therapy (e.g., thyroid hormone, insulin, corticosteroids foradrenal/pituitary insufficiency).

• History of non-infectious pneumonitis requiring systemic glucocorticoid therapy orinterstitial lung disease.

• History of severe bleeding tendency, coagulopathy, or long-term anticoagulationtherapy (e.g., atrial fibrillation with CHADS2 score ≥2).

• Uncontrolled comorbidities, including but not limited to decompensated livercirrhosis, nephrotic syndrome, uncontrolled metabolic disorders, severe activepeptic ulcer disease, or psychiatric/social conditions limiting compliance.

• History of myocarditis, cardiomyopathy, malignant arrhythmias; hospitalization forunstable angina, congestive heart failure, or vascular diseases (e.g., aorticaneurysm requiring surgery) within 12 months before study treatment.

• History of inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis,chronic diarrhea).

• Severe infection within four weeks before study treatment, including sepsis orsevere pneumonia requiring hospitalization; active infection requiring systemictherapy within ten days before study treatment (excluding antiviral therapy for HBVor HCV).

• Major surgery or severe trauma within 30 days before study treatment; minor surgery (excluding peripheral venous catheterization) within three days before studytreatment.

• Immunodeficiency history, positive HIV test, or long-term use of systemiccorticosteroids or immunosuppressants.

• Active tuberculosis or suspected TB requiring clinical exclusion; known activesyphilis infection.

• History of allogeneic organ or hematopoietic stem cell transplantation.

• Untreated active HBV infection (HBsAg-positive with HBV-DNA > 1000 copies/ml or 200IU/ml); active HCV infection (HCV antibody-positive with detectable HCV-RNA).

• Live vaccine administration within 30 days before study treatment or planned duringthe study period.

• Known hypersensitivity to any study drug component or history of severehypersensitivity reactions to monoclonal antibodies.

• History of psychiatric disorders, substance abuse, alcohol dependence, or drugaddiction.

• Pregnant or breastfeeding women.

• Any disease, treatment, or laboratory abnormality that may confound study results,interfere with full study participation, or is not in the participant's bestinterest.

• Non-malignant or tumor-related systemic diseases or symptoms causing high medicalrisk or uncertainty in survival assessment.