Neoadjuvant Iparomlimab/Tuvonralimab Plus CAPEOX Versus Iparomlimab/Tuvonralimab Plus CAPEOX and Propranolol for Locally Advanced pMMR Colon Cancer: A Prospective, Single-Center, Multi-Cohort Study

Inclusion Criteria

Participants must meet all of the following:

1. Diagnosis / Stage: Histologically confirmed and radiologically assessed colon adenocarcinoma that is T4, or T3 with lymph node metastasis, with tumor location ≥10 cm from the anal verge, and clinical TNM staging per AJCC/UICC 8th edition.
2. Measurable disease: At least one measurable lesion per RECIST v1.1 (non-lymph node lesion long axis ≥10 mm on CT; lymph node lesion short axis ≥15 mm on CT).
3. pMMR/MSS confirmation: pMMR by IHC on colonoscopy biopsy (MMR proteins by immunohistochemistry), or MSS/MSS-L by PCR or NGS.
4. Treatment-naïve for current colon cancer: No prior anti-tumor treatment for colon cancer. (If Lynch syndrome, no anti-tumor treatment for the current diagnosis.)
5. Age: 18 to 75 years, any sex.
6. Performance status / organ function: ECOG 0-1 with adequate organ and bone marrow function.
7. Informed consent: Written informed consent signed before enrollment.
8. Life expectancy: Expected survival \>12 weeks.
9. Hematology and chemistry (without blood products or growth factors within 14 days):

   * Hemoglobin ≥60 g/L
   * ANC ≥1.5 × 10⁹/L
   * Platelets ≥75 × 10⁹/L
   * Serum creatinine ≤1.5 × ULN or creatinine clearance ≥50 mL/min (Cockcroft-Gault)
   * Total bilirubin ≤1.5 × ULN
   * AST or ALT ≤2.5 × ULN (if abnormal due to liver metastasis, ≤5 × ULN)
   * Urine protein \<2+; if ≥2+, 24-hour urine protein ≤1 g
10. Coagulation / bleeding-thrombosis status: No active bleeding and no thrombotic disease; patients may be eligible if thrombosis is treated and stable for ≥3 months. Must meet:

    * INR ≤1.5 × ULN
    * APTT ≤1.5 × ULN
    * PT ≤1.5 × ULN
11. Thyroid function within normal range:

    * Free T4 12-22 pmol/L
    * Free T3 2.8-7.1 pmol/L
    * TSH 0.27-4.2 mIU/L
12. Blood pressure requirement (screening): Average seated BP 100-150 / 60-90 mmHg, and 24-hour ambulatory BP below the threshold for Grade I hypertension.
13. Contraception / pregnancy test (for women of childbearing potential): Must use medically approved contraception during treatment and for 3 months after; pregnancy test (serum or urine HCG negative within 7 days prior to enrollment); not breastfeeding.
14. Compliance: Willing and able to comply with study procedures and safety/survival follow-up.

Exclusion Criteria

Participants meeting any of the following are excluded:

1. History of allergic disease, severe drug allergy, known allergy to macromolecular protein products, or allergy to Iparomlimab/Tuvonralimab (protocol wording originally referenced the Chinese drug name).
2. Cardiopulmonary insufficiency or hepatic/renal insufficiency such that CAPEOX cannot be tolerated; known allergy to oxaliplatin or capecitabine.
3. Presence of distant metastasis.
4. Any of the following complications:

   * Major GI bleeding, perforation, or GI obstruction (including paralytic ileus)
   * Symptomatic heart disease (including unstable angina, myocardial infarction, heart failure)
   * Uncontrolled diabetes, hypertension, or hypotension
   * Uncontrolled diarrhea that interferes with daily activities despite adequate treatment
   * Use of immunosuppressants or systemic/absorbable local steroids for immunosuppression (\>10 mg/day prednisone equivalent) and still using within 2 weeks before enrollment
5. Poorly controlled cardiac symptoms or clinically significant heart disease, including:

   * NYHA class \>II heart failure
   * Unstable angina
   * Myocardial infarction within 1 year
   * Clinically significant supraventricular or ventricular arrhythmia requiring treatment/intervention
6. Prior or current thyroid dysfunction that cannot be maintained within normal range despite medication.
7. Use of traditional Chinese immune modulators within 2 weeks before treatment, or receipt of systemic anti-tumor therapy (chemotherapy, immunotherapy, biologic therapy, etc.) or TCM anti-tumor therapy within 4 weeks before treatment.
8. Active infection, or unexplained fever \>38.5°C during screening or before first dose (tumor-related fever may be allowed per investigator judgment).
9. History or current objective evidence of pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-related pneumonitis, known active pulmonary tuberculosis, severely impaired lung function, etc.
10. Congenital or acquired immunodeficiency, e.g., HIV infection (HIV 1/2 antibody positive).
11. Acute or chronic active HBV: HBsAg(+) or HBcAb(+) requires HBV DNA testing. Eligible only if HBV DNA \<2×10³ copies/mL or \<200 IU/mL or below LLOD; HBsAg(+) must receive anti-HBV therapy during study treatment; HBcAb(+)/HBsAg(-)/anti-HBs(-) with negative viral load does not require prophylaxis but requires close monitoring.
12. Acute or chronic active HCV: HCV antibody positive and HCV RNA above LLOD.
13. Receipt of a live vaccine within 4 weeks prior to study drug or anticipated need for live vaccination during the study.
14. Known history of psychoactive substance abuse, alcoholism, or drug abuse.
15. Pregnant or breastfeeding women, or men/women unwilling to use contraception.
16. History of allergy to β-blockers.
17. Asthma, COPD, or other respiratory disease requiring bronchodilator therapy.
18. Definite history of hypertension (without antihypertensives: non-same-day 3 measurements with SBP ≥140 mmHg and/or DBP ≥100 mmHg, or currently receiving antihypertensive therapy).
19. Clear history of hypotension; baseline SBP \<90 mmHg or DBP \<60 mmHg.
20. Any other condition judged by the investigator to warrant exclusion (e.g., factors that may force early termination of study participation).