This prospective, randomized phase II trial is designed to evaluate whether low-dose short-course radiotherapy differs from common-dose short-course radiotherapy in terms of efficacy when both regimens are sequentially combined with CAPOX, a PD-1 monoclonal antibody, and interleukin-2 (IL-2) in patients with locally advanced rectal cancer. The study is based on findings from our previous single-center, single-arm PRIDE01 study, in which neoadjuvant short-course radiotherapy followed by systemic chemoimmunotherapy and IL-2 demonstrated encouraging antitumor activity relative to historical short-course radiotherapy-based approaches. The current trial aims to provide more robust clinical evidence regarding the potential role of low-dose radiotherapy combined with IL-2 as a sensitization strategy in multimodal neoadjuvant therapy. By comparing complete response rates between the two radiotherapy dose levels, this study may help define an optimized neoadjuvant approach and support future organ-preservation strategies for patients with locally advanced rectal cancer.

Standard multimodality treatment, including neoadjuvant chemoradiotherapy or total neoadjuvant therapy followed by total mesorectal excision, has improved LARC control and radical resection rates. However, several important clinical challenges remain, including suboptimal complete response rates, impaired sphincter and organ preservation, treatment-related toxicity, distant metastasis, and limited improvement in long-term survival for some patients. Although total neoadjuvant therapy has further improved systemic disease control by delivering chemotherapy and radiation therapy before surgery, the optimal intensity and sequencing of radiation therapy, chemotherapy, and immunotherapy remain to be defined.

Immune checkpoint blockade (ICB) has transformed the treatment landscape of colorectal cancer with deficient mismatch repair or microsatellite instability-high disease. However, this subgroup accounts for only a small proportion of rectal cancers, while the majority of patients have proficient mismatch repair or microsatellite-stable tumors and derive limited benefit from single-agent PD-1 or PD-L1 inhibition. Immune resistance in microsatellite-stable colorectal cancer is closely associated with insufficient effector T-cell infiltration, T-cell dysfunction or exhaustion, and an immunosuppressive tumor microenvironment. Therefore, strategies that enhance tumor antigen release, promote immune-cell infiltration, reverse local immunosuppression, and restore cytotoxic T-cell function may improve the efficacy of immunotherapy in locally advanced rectal cancer.

Radiation therapy can induce immunogenic tumor-cell death, increase antigen presentation, remodel the tumor microenvironment, and promote immune-cell recruitment. Short-course radiation therapy is an established neoadjuvant radiation strategy for locally advanced rectal cancer and offers advantages including a shorter treatment duration and greater feasibility for integration with systemic therapy. In addition, oxaliplatin-based chemotherapy such as CAPOX may contribute to tumor-cell killing and immune modulation. Early clinical studies combining neoadjuvant chemoradiotherapy or short-course radiation therapy with PD-1 blockade have shown encouraging pathological complete response rates in patients with proficient mismatch repair or microsatellite-stable locally advanced rectal cancer, supporting further investigation of radiation-based immunomodulatory strategies.

Interleukin-2 is a key cytokine involved in T-cell proliferation, cytotoxic T-lymphocyte activation, natural killer cell function, and antitumor immunity. Although high-dose IL-2 has historically been limited by substantial toxicity, low-dose or modified IL-2-based approaches may enhance antitumor immune responses with improved tolerability. Preclinical and translational evidence suggests that IL-2 may synergize with PD-1 blockade by expanding activated effector T cells and supporting reinvigoration of exhausted T-cell populations. When integrated with radiation therapy, IL-2 may further amplify antitumor immunity by promoting immune-cell activation in the context of increased antigen release and local inflammatory priming.

Our previous single-center, single-arm PRIDE-01 study evaluated neoadjuvant short-course radiation therapy followed by CAPOX, PD-1 blockade, and IL-2 in patients with locally advanced rectal cancer and showed encouraging antitumor activity and complete response outcomes compared with historical short-course radiation therapy-based approaches. These findings provide the clinical rationale for further evaluation of this multimodal neoadjuvant strategy in a prospective randomized setting.

This single-center, prospective, randomized, open-label phase II trial is designed to compare low-dose versus standard-dose short-course radiation therapy, each followed by CAPOX, a PD-1 monoclonal antibody, and IL-2, in patients with locally advanced rectal cancer. Eligible patients will be randomly assigned to receive either low-dose short-course radiation therapy or standard-dose short-course radiation therapy, followed by sequential systemic therapy consisting of CAPOX, PD-1 blockade, and IL-2. The study aims to determine whether low-dose short-course radiation therapy combined with IL-2-containing chemoimmunotherapy can achieve comparable or favorable complete response outcomes while potentially reducing radiation-related toxicity.

The primary objective is to compare complete response rates between the two treatment groups, including pathological complete response in patients undergoing surgery and clinical complete response in patients managed with a watch-and-wait strategy. Secondary objectives include evaluation of tumor response, organ preservation, sphincter preservation, disease-free survival, event-free survival, overall survival, surgical outcomes, treatment compliance, and safety. Exploratory translational analyses will assess dynamic changes in peripheral immune-cell subsets, cytokine profiles, circulating biomarkers, tumor immune microenvironment features, and their associations with treatment response.

By comparing different doses of short-course radiation therapy within the same CAPOX, PD-1 blockade, and IL-2-containing neoadjuvant framework, this trial seeks to generate higher-level evidence for an optimized immunomodulatory neoadjuvant strategy in locally advanced rectal cancer. The results may help define whether low-dose radiation therapy combined with IL-2 can serve as a sensitizing approach to enhance response while supporting future organ-preserving treatment strategies.

Inclusion Criteria:

1. Male and female patients aged 18 to 70 years.
2. Histologically confirmed rectal adenocarcinoma with the distal margin of the tumor located within 12 cm of the anal verge.
3. MRI-based clinical stage T3-T4 or any T with lymph node-positive (N+) disease.
4. Adequate hematologic, hepatic, and renal function defined as: absolute neutrophil count >=1.5 x 10^9/L; platelet count >=75 x 10^9/L; serum total bilirubin <=1.5 x upper normal limit (UNL); aspartate aminotransferase <=2.5 x UNL; alanine aminotransferase <=2.5 x UNL; serum creatinine <=1.5 x UNL.
5. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.

Exclusion Criteria:

1. Metastatic disease (Stage IV).
2. Recurrent rectal cancer.
3. Concurrent active bleeding, perforation, or other complicated conditions requiring emergency surgery.
4. Prior systemic anticancer therapy for rectal cancer.
5. Presence of another non-colorectal neoplastic disease at the same time.
6. Patients with any active autoimmune disease or a history of autoimmune disease requiring steroids or immunomodulatory therapy.
7. Patients with interstitial lung disease, non-infectious pneumonitis, or uncontrolled systemic diseases (e.g., diabetes mellitus, hypertension, pulmonary fibrosis, and acute pneumonitis).
8. Any unresolved grade >=2 toxicity (according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0) resulting from previous treatment, except for anemia, alopecia, and skin hyperpigmentation.
9. Prior treatment with anti-programmed death-1 (PD-1)/PD-L1 antibody or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody.
10. Pregnant or breastfeeding women.
11. Known or tested positive for human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS).
12. Known or suspected history of allergy to any of the relevant drugs used in the study.