The ONTOP study is a prospective, single-arm, open-label phase II clinical trial. A total of 32 patients with advanced MSS/pMMR colorectal cancer who have failed first-line treatment will receive second-line standard treatment combined with Ongericimab and toripalimab. Among them, patients who received irinotecan-containing treatment in the first line will be administered the regimen of Ongericimab + toripalimab + bevacizumab + FOLFOX. Patients who received oxaliplatin-containing treatment in the first line will be administered the regimen of Ongericimab + toripalimab + bevacizumab + FOLFIRI. Treatment will continue until disease progression, initiation of new anti-tumor treatment, active request of the subject, or determination by the investigator that study drug administration needs to be terminated. The primary study endpoint is the objective response rate (ORR), and the secondary study endpoints include duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety, etc.

Inclusion Criteria:

1. Subjects aged 18-75 years (inclusive of 18 and 75 years) at the time of signing the informed consent, regardless of gender.
2. Histologically confirmed MSS/pMMR colorectal or rectal cancer, who have progressed on first-line fluoropyrimidine - based combination therapy (including progression during maintenance therapy). If FOLFOXIRI was received in the first - line, screening is not allowed; if progression occurred during neoadjuvant/adjuvant therapy or within 6 months after the last dose, it is considered first-line treatment failure, and the patient is eligible for enrollment.
3. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.
4. Predicted survival ≥ 12 weeks.
5. At least 1 measurable lesion according to RECIST 1.1 evaluation criteria.
6. Adequate organ function；
7. Female or male subjects with childbearing potential must agree to have no childbearing plans within 6 months after the end of the last dose during the study period and be willing to take highly effective contraceptive measures together with their partners. For female subjects with childbearing potential, the serum pregnancy test must be negative within 7 days before the first dose, and they must be non - lactating.
8. Be able to provide a signed informed consent form, including complying with the requirements and restrictions listed in the Informed Consent Form (ICF) and this protocol.

Exclusion Criteria:

1. Presence of leptomeningeal metastasis; presence of active brain metastasis, defined as untreated and/or having clinical symptoms, or requiring glucocorticoids or antiepileptic drugs to control related symptoms. For those who have received local treatments such as surgery or radiotherapy, if the screening - period imaging assessment shows no evidence of progression for at least four weeks and symptoms disappear (except for residual signs or symptoms related to brain metastasis), no glucocorticoid treatment is needed for at least 2 weeks, and the acute toxicities related to previous treatments have recovered, enrollment is allowed.

2. Presence of pleural effusion, peritoneal effusion, or pericardial effusion with clinical symptoms or requiring repeated management (such as puncture or drainage).

3. History of immunodeficiency disorders, including positive detection of human immunodeficiency virus (HIV), or known allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation.

4. History of severe cardiovascular diseases, including but not limited to: myocardial infarction within 6 months before the first study drug administration, severe/unstable angina pectoris, congestive heart failure (NYHA heart function class ≥2), severe supraventricular or ventricular arrhythmia, aortic aneurysm requiring surgical repair, any arterial thromboembolic event, grade 3 or above venous thromboembolic event, transient ischemic attack, cerebrovascular accident.

5. Presence of abdominal or tracheoesophageal fistula, gastrointestinal (GI) perforation, or intra-abdominal abscess within 6 months before the first drug administration.

6. Severe infection within 28 days before the first study drug administration (CTCAE 5.0 ≥ grade 2), such as severe pneumonia requiring hospitalization, bacteremia, infectious complications, etc.; active infection requiring intravenous anti-infection treatment or unexplained fever > 38.5°C within 2 weeks before the first study drug administration (judged by the researcher; fever caused by the tumor in the subject can be enrolled).

7. Presence of active tuberculosis, hepatitis B (hepatitis B surface antigen [HBsAg] positive and HBV DNA higher than the lower limit of detection of the research center), hepatitis C (HCV Ab positive and HCV RNA higher than the lower limit of detection of the research center).

8. History of another primary malignant tumor, except for those who have received radical treatment before the first administration of the study intervention, have no known active disease (for more than 5 years), and have a low potential recurrence risk (such as skin basal cell carcinoma and cutaneous squamous cell carcinoma that have received curative treatment).

9. The following situations do not allow screening:

   1. Screening period imaging shows that the tumor encircles important blood vessels or has obvious necrosis and cavity, and the researcher deems it may cause bleeding risk;
   2. Clinical signs or symptoms of intestinal obstruction and/or gastrointestinal obstruction within 6 months before the first drug administration, including incomplete obstruction related to the underlying disease;
   3. Presence of severe, unhealed, or ruptured wounds, active ulcers, or untreated fractures;
   4. Clinically significant hemoptysis (≥1/2 tea spoon) or tumor bleeding for any reason within 1 month before the first drug administration;
   5. Presence of poorly controlled hypertension (systolic blood pressure ≥150 mmHg and/or diastolic blood pressure > 100 mmHg), or history of hypertensive emergency or hypertensive encephalopathy;
   6. Subjects with other conditions judged by the investigator to be unsuitable for bevacizumab therapy.

10. Previous antineoplastic treatment toxicity has not recovered to grade 1 specified in CTCAE 5.0 or the level specified in the enrollment/exclusion criteria. Except for the following situations: if the researcher judges that the related toxicity is well-controlled and does not affect the safety and compliance of the subject using the study drug, screening is allowed.

11. Previous occurrence of drug-related adverse events leading to permanent drug discontinuation during treatment with bevacizumab and similar drugs.

12. Received the following drugs or treatments before the first drug administration:

    1. Received chemotherapy, immunotherapy, radiotherapy or other anti-tumor therapies within 14 days prior to the first dose, including oral fluoropyrimidines, small-molecule targeted agents, traditional Chinese medicines with anti-tumor indications, and palliative radiotherapy;
    2. Underwent major surgery within 28 days prior to the first dose, or received core needle biopsy or other minor surgery (excluding placement of vascular access devices) within 7 days before the initiation of study treatment;
    3. Subjects who used systemic corticosteroids (≥10 mg prednisone equivalent per day) or other immunosuppressants for systemic treatment within 2 weeks before the first drug administration; inhalation or local use of corticosteroids or preventive medication (such as for infusion reaction/hypersensitivity reaction) is allowed;
    4. Received any live vaccine or attenuated vaccine within 28 days before the first drug administration, or need to receive live vaccines during the study period.

13. Used antiplatelet therapy or anticoagulant therapy for therapeutic purposes within 10 days before the first drug administration.

14. Pregnant or lactating women.

15. Presence of other severe physical or mental diseases or abnormal laboratory examinations, which may increase the risk of participating in the study, affect treatment compliance, or interfere with the study results, and are judged by the researcher as unsuitable for participating in the study.