Inclusion Criteria:
* Has fully understood the study and voluntarily signed the informed consent form.
* Aged 18-75 years, with no restriction on sex.
* Histologically or cytologically confirmed advanced colorectal adenocarcinoma.
* Has experienced disease progression after receiving at least two lines of standard therapy, or has developed intolerable toxicity from standard therapy. Standard therapy is defined as prior treatment with fluoropyrimidine plus leucovorin plus a platinum agent or irinotecan, with or without cetuximab or bevacizumab.
* Has at least one measurable lesion according to RECIST version 1.1.
* ECOG performance status of 0-1.
* Estimated life expectancy of ≥3 months.
* Willing and able to comply with study procedures and receive treatment, including radiotherapy, immunotherapy, targeted therapy, and follow-up.
* Has adequate organ function, defined as:
* Absolute neutrophil count (ANC) ≥1.5 × 10⁹/L;
* Platelet count (PLT) ≥80 × 10⁹/L;
* Hemoglobin (Hb) ≥90 g/L;
* Total bilirubin (TBil) ≤1.5 × the upper limit of normal (ULN);
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤1.5 × ULN, or ≤3 × ULN in patients with liver metastases;
* Serum creatinine ≤1.5 × ULN, or calculated creatinine clearance ≥50 mL/min;
* International normalized ratio (INR) ≤1.5 × ULN, and prothrombin time (PT) or activated partial thromboplastin time (APTT) ≤1.5 × ULN, unless the participant is receiving anticoagulant therapy;
* For participants positive for hepatitis B surface antigen (HBsAg), peripheral blood hepatitis B virus DNA (HBV-DNA) titer ≤1 × 10³ copies/L. Participants with HBsAg positivity and HBV-DNA titer ≥1 × 10³ copies/L may be enrolled if, in the investigator's judgment, their chronic hepatitis B is stable and does not pose an increased risk.
* Women of childbearing potential must agree to use appropriate contraception throughout the study. A serum or urine pregnancy test performed within 24 hours before initiation of chemotherapy must be negative.
* Female participants must not be breastfeeding.
Exclusion Criteria:
* Receipt of any investigational drug treatment within 4 weeks before the first administration of study treatment.
* Concurrent participation in another clinical study, unless it is an observational (non-interventional) study or the follow-up phase of an interventional clinical study.
* Receipt of brachytherapy, such as radioactive seed implantation, within 60 days before the first dose.
* Uncontrolled serious illness that, in the investigator's opinion, may impair the participant's ability to receive protocol-specified treatment, including severe cardiac disease, cerebrovascular disease, uncontrolled diabetes mellitus, uncontrolled hypertension, uncontrolled infection, or active peptic ulcer disease.
* Active, known, or suspected autoimmune disease, including but not limited to uveitis, enteritis, hepatitis, hypophysitis, nephritis, vasculitis, hyperthyroidism, hypothyroidism, and asthma requiring bronchodilator therapy. Participants with hypothyroidism requiring hormone replacement therapy and those with skin conditions not requiring systemic treatment, such as vitiligo, psoriasis, or alopecia, may be enrolled.
* Active tuberculosis infection. Participants with active pulmonary tuberculosis within 1 year will be excluded, even if treated. Participants with a history of active pulmonary tuberculosis more than 1 year before enrollment will also be excluded unless they can demonstrate completion of standard anti-tuberculosis therapy.
* Requirement for long-term systemic corticosteroid therapy at a dose equivalent to \>10 mg/day of prednisone, or any other form of immunosuppressive therapy. Participants receiving inhaled or topical corticosteroids may be enrolled.
* Uncontrolled cardiac disease, including New York Heart Association (NYHA) class II or higher heart failure; unstable angina; myocardial infarction within 1 year; clinically significant supraventricular or ventricular arrhythmias requiring treatment or intervention; dementia, altered mental status, or any psychiatric disorder that may impair comprehension, provision of informed consent, or completion of study questionnaires.
* History of another malignancy within 5 years before enrollment, except for adequately treated basal cell carcinoma or squamous cell carcinoma of the skin, localized prostate cancer after curative surgery, or ductal carcinoma in situ of the breast after curative treatment.
* Active gastric or duodenal ulcer, ulcerative colitis, or other gastrointestinal disease; unresected tumors with active bleeding; or any other condition considered by the investigator to pose a risk of gastrointestinal bleeding or perforation. Participants with prior gastrointestinal perforation or gastrointestinal fistula who have not recovered after surgery will be excluded.
* Positive hepatitis C virus (HCV) antibody or human immunodeficiency virus (HIV) antibody.
* Active infection requiring systemic treatment.
* Contraindication to penpulimab or fruquintinib, including a history of allergy or hypersensitivity to any component of either drug.
* Contraindication to radiotherapy, such as prior adequate-dose radiotherapy to the same site, severe radiation injury to the skin or local tissues/organs, or inability to tolerate re-irradiation.
* Any other condition that, in the investigator's judgment, makes the participant unsuitable for enrollment.
