SBRT Combined With CAPEOX, Bevacizumab, and PD-1 Inhibitor for the Treatment of RAS-Mutant, MSS-Type, Unresectable Metastatic Colorectal Cancer.

Colorectal cancer (CRC) is currently one of the most common malignant tumors of the digestive tract in clinical practice. According to the latest cancer data in China, CRC ranks as the fourth leading cause of cancer-related deaths, with both its incidence and mortality rates showing an increasing trend. The early diagnosis and treatment rates of CRC in China remain significantly lower compared to developed countries. Most patients are diagnosed at locally advanced or metastatic stages, resulting in poor treatment outcomes and prognosis. Among newly diagnosed cases, 20% already present with distant metastases (metastatic colorectal cancer, mCRC), with a 5-year survival rate below 20%.

The NCCN and CSCO guidelines recommend standard treatments for mCRC patients, including fluorouracil-, oxaliplatin-, and/or irinotecan-based chemotherapy regimens combined with angiogenesis-targeting agents (e.g., bevacizumab) or epidermal growth factor receptor (EGFR)-targeted therapies (e.g., cetuximab), depending on the patient's RAS and BRAF status. RAS mutations are present in 50-56% of mCRC cases. For RAS-mutant mCRC patients, bevacizumab combined with chemotherapy is the standard first-line treatment. However, these patients exhibit poorer prognoses and shorter survival times compared to those with RAS wild-type mCRC. Studies also indicate that RAS-mutant mCRC features an immunosuppressive tumor microenvironment. Thus, enhancing the efficacy of first-line therapy for this subgroup remains a major clinical challenge.

In recent years, immune checkpoint inhibitors (ICIs) have revolutionized treatment paradigms for several solid cancers, including melanoma and lung cancer, by inducing durable responses and significantly improving outcomes. Microsatellite instability-high (MSI-H) CRC, characterized by high tumor mutational burden and neoantigen production, activates the immune system and demonstrates high responsiveness to ICIs. Multiple immunotherapies have been approved for MSI-H CRC, markedly prolonging survival and improving quality of life. However, microsatellite stable (MSS) mCRC, accounting for approximately 95% of cases, is considered an immunologically "cold tumor" due to low tumor mutational burden and limited immune cell infiltration. Only a small subset of MSS patients, such as those with POLE/POLD1 mutations, may benefit from ICIs, whereas monotherapy with ICIs shows minimal efficacy in most MSS/pMMR tumors. Consequently, novel strategies are urgently needed to enhance immunotherapy responses in this subgroup.

Radiotherapy not only improves local tumor control by directly killing irradiated tumor cells but also activates systemic antitumor immunity through multiple mechanisms, potentially reducing metastatic risk and synergizing with immunotherapy. First, radiotherapy promotes the release of pro-phagocytic signals (e.g., calreticulin) while downregulating anti-phagocytic signals like CD47, enhancing macrophage-mediated tumor phagocytosis. Post-radiotherapy release of high-mobility group box 1 (HMGB1) and upregulation of MHC-I expression facilitate tumor antigen processing and presentation to CD8+ T cells. Additionally, radiation-induced DNA damage may generate neoantigens and trigger immune surveillance. Studies show that DNA repair-deficient tumor cells exhibit growth suppression in immunocompetent mice post-radiotherapy, a phenomenon absent in immunodeficient models, suggesting that accumulated mutations in repair-deficient cells increase neoantigen burden and drive immune responses. Radiation may also elevate mutational load, providing novel targets for immune recognition. Furthermore, radiotherapy modifies the tumor stromal microenvironment by inducing cytokine production. For instance, radiation promotes TNF release, significantly reducing myeloid-derived suppressor cell (MDSC) infiltration, while enhancing CXCL9/CXCL10 secretion to recruit cytotoxic T cells. Collectively, these mechanisms shift the immune milieu toward tumor elimination, providing a rationale for combining radiotherapy with immunotherapy.

Against this backdrop, we designed this study: Evaluation of the Efficacy and Safety of SBRT Combined with CAPEOX, Bevacizumab, and PD-1 Inhibitor in RAS-Mutant, Microsatellite Stable (MSS), and Unresectable Metastatic Colorectal Cancer (mCRC) : a Single-center, Single-arm, Open-label Clinical Trail.