Neoadjuvant Therapy for Locally Advanced Low Rectal Cancer (SMARTi-RC01)

Inclusion criteria

Participants must meet all of the following criteria to be eligible for the study:

• Age: 18 to 75 years old.
• Diagnosis: Pathologically confirmed rectal adenocarcinoma with proficient mismatch repair (pMMR) / microsatellite stable (MSS) status, based on biopsy of the primary tumor.
• Disease Stage: Untreated, preoperative clinical stage cT2-T4 and/or N+, M0 (AJCC 8th edition), unsuitable for initial local excision to achieve radical cure.
• Tumor Location: Tumor within 8 cm from the anal verge, or assessed by surgeons as not suitable for immediate sphincter-preserving surgery.
• Organ Preservation Intent: Strong desire for sphincter preservation and willingness to accept close surveillance for at least 2 years after chemoradiotherapy.
• Surgical Candidacy: Agrees to undergo radical surgery and judged by surgeon to have no contraindication to surgery.
• Cancer History: No concurrent multiple primary malignancies.
• Measurable Lesions: At least one measurable or evaluable lesion according to RECIST v1.1 criteria.
• Life Expectancy: ≥ 3 months.
• Performance Status: ECOG performance status score of 0-1.
• Compliance: Good compliance and willingness to sign written informed consent.

Exclusion criteria

Participants will be excluded if any of the following conditions apply:

• Molecular Subtype: Rectal cancer with deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) status.
• Autoimmune Disease: Active, known, or suspected autoimmune disease.
• Immunodeficiency: Known history of primary immunodeficiency.
• Transplant History: History of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation.
• Pregnancy or Lactation: Pregnant or breastfeeding women.
• Urgent Surgical Indications: Intestinal perforation, gastrointestinal bleeding, or other conditions requiring emergency surgery.
• Uncontrolled Comorbidities, including but not limited to:

HIV infection (HIV antibody positive) Active or poorly controlled severe infection Active hepatitis Severe or uncontrolled systemic diseases (e.g., severe psychiatric or neurological disorders, epilepsy, dementia, unstable or decompensated respiratory, cardiovascular, hepatic, or renal disease, uncontrolled hypertension ≥ CTCAE Grade 2 despite medication) Active bleeding or recent thrombotic disease requiring therapeutic anticoagulation, or bleeding tendency, or coagulation abnormalities (INR > 1.5 × ULN, APTT > 1.5 × ULN)

• Laboratory Abnormalities at Baseline:

Hemoglobin < 80 g/L Absolute neutrophil count (ANC) < 1.5 × 10⁹/L Platelets < 80 × 10⁹/L ALT or AST > 2.5 × ULN ALP > 2.5 × ULN Total bilirubin ≥ 1.5 × ULN Serum creatinine ≥ 1 × ULN

• Allergy: Known hypersensitivity to any component of the investigational drugs.
• Other Clinical Trial Participation: Currently enrolled in another interventional drug clinical trial.
• Other Conditions: Any other condition judged by the investigator to make the patient unsuitable for the study.