The goal of this prospective, single-center, multi-cohort clinical trial is to evaluate the efficacy and safety of neoadjuvant Iparomlimab/Tuvonralimab combined with CAPEOX, with or without propranolol, in patients with locally advanced pMMR (MSS) colon cancer. The main questions it aims to answer are:

• What is the major pathological response (MPR) rate after neoadjuvant treatment and curative surgery (e.g., ≤10% viable tumor cells in the resected primary tumor)?
• What are the key secondary outcomes (e.g., R0 resection rate, tumor regression grade, objective response rate, disease-free survival) and the safety/tolerability profile of these neoadjuvant regimens? If there is a comparison group: Researchers will compare Cohort A (Iparomlimab/Tuvonralimab + CAPEOX) versus Cohort B (Iparomlimab/Tuvonralimab + CAPEOX + propranolol) to see whether adding propranolol improves pathological and clinical responses while maintaining acceptable safety.

Participants will:

• Receive neoadjuvant Iparomlimab/Tuvonralimab + CAPEOX for a protocol-defined number of cycles, with or without propranolol depending on cohort assignment.
• Undergo curative-intent surgical resection after completing neoadjuvant therapy.
• Be followed for postoperative treatment, adverse events, and longer-term outcomes (e.g., recurrence and survival), and may contribute tumor/blood samples for exploratory biomarker analyses related to treatment response.

This prospective, single-center, multi-cohort study evaluates a neoadjuvant treatment strategy for patients with locally advanced pMMR/MSS colon cancer, a population known to have limited sensitivity to immune checkpoint blockade alone.

The study investigates whether combining dual immune checkpoint inhibition (PD-1 and CTLA-4 blockade using Iparomlimab and Tuvonralimab) with standard chemotherapy (CAPEOX) can enhance treatment response. In addition, the study explores whether modulation of the tumor microenvironment through β-adrenergic blockade (propranolol) may further improve antitumor immune activity.

Eligible participants will be assigned to one of two treatment cohorts:

Cohort A: Neoadjuvant Iparomlimab/Tuvonralimab combined with CAPEOX Cohort B: Neoadjuvant Iparomlimab/Tuvonralimab combined with CAPEOX plus propranolol All participants will receive four cycles of neoadjuvant therapy administered every three weeks. Immunotherapy is delivered intravenously on Day 1 of each cycle, while CAPEOX is administered according to standard dosing schedules. In Cohort B, propranolol is administered orally during the chemotherapy period of each cycle.

Following completion of neoadjuvant treatment, patients will undergo curative-intent surgical resection within a protocol-defined time window. Postoperative management, including adjuvant therapy, will be determined by the treating investigator according to clinical judgment and standard practice.

Tumor response will be assessed during treatment and prior to surgery using radiographic imaging. Pathologic response will be evaluated on surgical specimens to determine treatment efficacy.

In addition to clinical outcomes, this study includes exploratory translational research components. Tumor tissue and blood samples will be collected to investigate immune-related biomarkers and molecular features associated with treatment response. These analyses include RNA sequencing, immunohistochemistry, and flow cytometry-based immune profiling.

The study uses a staged design with early stopping rules based on pathologic response, allowing for preliminary assessment of treatment activity before full cohort expansion.

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).