Standard treatment for patients with proficient mismatch repair (pMMR) / microsatellite stable (MSS) locally advanced rectal cancer (LARC) consists primarily of neoadjuvant chemoradiotherapy followed by radical surgery. Several studies (including the UNION, STELLAR, TORCH, and SPRING-01 trials, etc) have demonstrated that the neoadjuvant strategy of short-course radiotherapy followed by chemotherapy combined with immunotherapy can improve pCR rate in patients with pMMR/MSS LARC, and might also provide higher organ preservation rates and long-term survival benefits. The study aims to explore the efficacy and safety of a TNT regimen comprising short-course radiotherapy combined with chemotherapy, cetuximab N01 (for patients with wild-type RAS/BRAF) or bevacizumab (for patients with mutant RAS/BRAF), and sintilimab in patients with high-risk LARC.

Inclusion Criteria:

• Voluntarily signed the informed consent form.
• Aged 18-75 years (inclusive of 18 and 75 years).
• pMMR/MSS.
• Middle or low rectal cancer located ≤10 cm from the anal verge as assessed by MRI.
• Histopathologically confirmed locally advanced rectal adenocarcinoma and high-risk features confirmed by pelvic MRI (meeting any of the following criteria: clinical stage cT3N+ or cT4N0/+; MRF+ or EMVI+; enlarged lateral pelvic lymph nodes).
• ECOG PS of 0-1.
• Expected survival ≥2 years.
• No prior anti-tumor therapy.
• At least one measurable lesion with a longest diameter ≥10 mm measured by MRI (by RECIST version 1.1).
• Organ functions meeting the following requirements (no blood products or cell growth factors allowed within 14 days prior to enrollment):

Absolute neutrophil count ≥1.5×10⁹/L; Platelet count ≥100×10⁹/L; Hemoglobin ≥90 g/L; Total bilirubin <1.5×ULN; ALT and/or AST <2.5×ULN; Serum creatinine <1.5×ULN; Creatinine clearance ≥50 mL/min.

• Women of childbearing potential must use effective contraceptive measures.
• Good compliance and willingness to comply with follow-up requirements.

Exclusion Criteria:

• Unable to comply with the study protocol or study procedures.
• Patients with contraindications to surgery.
• Patients with metastatic disease or recurrent rectal cancer.
• Uncontrolled active autoimmune disease or active inflammatory disease at enrollment, or receiving immunosuppressive therapy.
• History of organ transplantation.
• Known interstitial lung disease (ILD) or unexplained persistent cough and dyspnea.
• Patients with familial adenomatous polyposis (FAP), hereditary non-polyposis colorectal cancer (HNPCC), active Crohn's disease, or active ulcerative colitis.
• Other malignancy diagnosed within 5 years prior to enrollment, except for radically resected basal cell or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix.
• Severe cardiovascular disease within 6 months prior to enrollment, including unstable angina pectoris or myocardial infarction.
• Subjects with hypersensitivity to the investigational product or any of its excipients.
• Participation in another clinical trial of an unapproved/investigational drug within 4 weeks prior to enrollment and having received the corresponding investigational product.
• Clinically significant electrolyte abnormalities judged by the investigator.
• Uncontrolled hypertension prior to enrollment, defined as systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg despite medication.
• Poorly controlled diabetes mellitus prior to enrollment (fasting glucose concentration ≥ CTCAE Grade 2 after standard treatment).
• Any disease or condition affecting drug absorption prior to enrollment, or inability of the patient to take oral medication.
• Active gastrointestinal diseases such as gastric and duodenal ulcer, ulcerative colitis prior to enrollment, or other conditions judged by the investigator that may cause gastrointestinal bleeding or perforation.
• Severe active bleeding within 3 months prior to enrollment, hemoptysis (>5 mL fresh blood within 4 weeks), or thromboembolic event (including stroke and/or transient ischemic attack) within 12 months.
• Clinically significant cardiovascular disease including but not limited to: acute myocardial infarction, severe/unstable angina pectoris, or coronary artery bypass grafting within 6 months prior to enrollment; congestive heart failure with New York Heart Association (NYHA) classification > Grade 2; ventricular arrhythmia requiring pharmacotherapy; left ventricular ejection fraction (LVEF) < 50%.
• Active or uncontrolled severe infection (≥ CTCAE v5.0 Grade 2).
• Known human immunodeficiency virus (HIV) infection. Known clinically significant liver disease history, including viral hepatitis:
• Hepatitis B virus (HBV) carriers with active HBV infection (HBV DNA positive: >1×10⁴ copies/mL or >2000 IU/mL);
• Known hepatitis C virus (HCV) infection with positive HCV RNA (>1×10³ copies/mL).
• Unresolved toxicities higher than CTCAE v5.0 Grade 1 resulting from any prior anti-cancer therapy, excluding alopecia, lymphopenia, and oxaliplatin-induced neurotoxicity ≤ Grade 2.
• Female subjects who are pregnant (positive pregnancy test before treatment) or breastfeeding.
• Urinalysis showing urine protein ≥ 2+ and 24-hour urinary protein > 1.0 g.
• Any other disease, clinically significant metabolic abnormality, physical examination abnormality, or laboratory abnormality that, in the investigator's judgment, renders the patient unsuitable for the study drug (e.g., seizure disorder requiring treatment), interferes with the interpretation of study results, or places the patient at high risk.
• Patients considered unsuitable for inclusion in this study by the investigator.