Short-course Radiotherapy Combined With Retlirafusp Alfa and CAPOX Chemotherapy as Neoadjuvant Therapy for Locally Advanced Rectal Cancer: A Prospective, Single-arm, Phase II Clinical Study

Inclusion Criteria:

1. Age 18-70 years, male or female.
2. Histologically or cytologically confirmed rectal adenocarcinoma, stage T3N+M0 or T4NanyM0 (AJCC/UICC TNM 8th edition), with measurable lesion(s) per RECIST 1.1.
3. Tumor lower border 5-10 cm from the anal verge.
4. Expected to achieve R0 resection after neoadjuvant therapy, and planned for surgery thereafter.
5. ECOG PS 0-1.
6. No prior anti-tumor therapy for rectal cancer, including radiotherapy, chemotherapy, immune checkpoint inhibitors, or surgery.

7. Adequate organ function (without blood product or growth factor support during screening):

   ANC ≥1.5×10⁹/L; platelets ≥100×10⁹/L; hemoglobin ≥8.5 g/dL.

   TSH ≤1×ULN (if abnormal, T3/T4 must be within normal limits for enrollment).

   Bilirubin ≤1.5×ULN; ALT and AST ≤2.5×ULN.

   Serum creatinine ≤1.5×ULN or CrCl ≥50 mL/min (Cockcroft-Gault formula).

   INR ≤1.5×ULN; APTT ≤1.5×ULN.

8. Negative pregnancy test (β-hCG) for women of childbearing potential before treatment initiation.Women of childbearing potential and men (who are sexually active with women of childbearing potential) must agree to use effective contraception continuously during treatment and for 6 months after the last dose.
9. Voluntary participation with written informed consent.

Exclusion Criteria:

1. History of other malignancies within the past 5 years, except adequately treated cervical carcinoma in situ, cutaneous squamous cell carcinoma, or basal cell carcinoma.
2. Major surgery or severe trauma within 4 weeks prior to first study drug administration.
3. Systemic corticosteroids (equivalent to prednisone >10 mg/day) or other immunosuppressive therapy within 2 weeks prior to study drug administration.
4. Active, known, or suspected autoimmune disease. Patients with stable conditions not requiring systemic immunosuppression (e.g., type 1 diabetes, hypothyroidism on hormone replacement, or skin disorders without systemic treatment) are eligible.
5. Immunodeficiency, including HIV positivity, other acquired/congenital immune deficiencies, or history of organ or allogeneic bone marrow transplantation.
6. Congestive heart failure, uncontrolled arrhythmia, myocardial infarction within 6 months, unstable angina, stroke, or other conditions precluding surgery.
7. Pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-related pneumonitis, or severely impaired pulmonary function.
8. Uncontrolled symptomatic brain metastases, poorly controlled psychiatric disorders, or severe intellectual/cognitive impairment.
9. Known substance abuse or drug addiction.
10. Clinically significant bleeding symptoms or clear bleeding tendency within 3 months prior to enrollment.
11. Severe active infection requiring IV antibiotics during screening.
12. Known hypersensitivity to Retlirafusp alfa or any excipients (polysorbate 80 (II), sucrose, citric acid, sodium citrate, water for injection, etc.), or severe allergic reactions to other monoclonal antibodies.
13. Active hepatitis B (HBV DNA >2000 IU/mL or 10⁴ copies/mL), or hepatitis C antibody-positive with HCV RNA above the lower limit of detection.
14. Receipt or planned receipt of live vaccine within 30 days prior to immunotherapy administration.
15. Intolerance to chemotherapy.
16. Inability to comply with the protocol or follow-up.
17. Other conditions deemed unsuitable for participation by the investigator.