General Commentary: Emerging strategies in colorectal cancer immunotherapy: enhancing efficacy and survival

Tao Li¹Bo Zhang^1*Li LI²Guoliang Wu¹Xiaoyao Chen¹

• ¹The First Affiliated Hospital of Shandong First Medical University, Shandong Provincial Qianfoshan Hospital, Jinan, China
• ²Shandong University of Traditional Chinese Medicine Affiliated Hospital, Jinan, China

The review's section on ICIs (Section 2) meticulously details the mechanisms of PD-1/PD-L1, CTLA-4, and LAG-3 inhibitors, underscoring their efficacy in dMMR/MSI-H CRC while noting limitations like immune-related adverse events (irAEs) and resistance. The authors reference landmark trials such as KEYNOTE-177 and CheckMate 142, which established pembrolizumab and nivolumab-based regimens as first-line options for MSI-H mCRC. Recent 2025 updates and FDA approvals have further solidified dual checkpoint blockade as a cornerstone of therapy. Notably, the FDA's 2025 approval of nivolumab plus ipilimumab (Opdivo + Yervoy) for first-line treatment of advanced dMMR/MSI-H CRC stems from the CheckMate-8HW trial, a phase III study involving over 700 patients [2]. Updated analyses revealed a median progression-free survival (PFS) exceeding 38 months with the combination versus 10 months with chemotherapy, with a hazard ratio of 0.21 (p<0.0001). Importantly, 80% of responders maintained responses beyond 2 years, suggesting curative potential in a subset of patients. This builds on the review's mention of CheckMate 142 by demonstrating superior overall survival (OS) benefits, with a 4-year OS rate of 71% in the combination arm. Clinically, this regimen addresses the review's concern about irAEs by optimizing dosing (low-dose ipilimumab), reducing grade 3-4 events to 23% compared to 32% in earlier cohorts. For LAG-3 inhibitors, the review highlights relatlimab's synergy with nivolumab in CheckMate 142, where the combination demonstrated an objective response rate (ORR) of 46% and a disease control rate of 62% in previously treated patients with microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR) metastatic colorectal cancer (mCRC) [3]. A 2025 update from the RELATIVITY-047 trial [4] in advanced melanoma reported an ORR of 43.9% with the combination versus 33.4% with nivolumab alone, with median duration of response not reached at a minimum follow-up of 45.3 months. Mechanistically, LAG-3 blockade mitigates T-cell exhaustion in the tumor microenvironment (TME), as evidenced by increased IFN-γ production and enhanced CD8+ T-cell infiltration in preclinical models and post-treatment biopsies [5]. However, a key scientific challenge remains: primary resistance in 20-30% of MSI-H patients, often linked to beta-2-microglobulin (B2M) mutations impairing antigen presentation [6]. Recent single-cell RNA sequencing studies have identified exhausted CD8+ subsets expressing TIM-3 as predictors of non-response to immunotherapy, paving the way for triple blockade trials combining PD-1, LAG-3, and TIM-3 inhibition [7]. In pMMR/MSS CRC (Section 3), the review astutely discusses combinations to "heat up" cold tumors. In alignment with this approach, the phase III STELLAR-303 trial [8] (NCT05425940) was designed to evaluate zanzalintinib, a novel tyrosine kinase inhibitor targeting VEGFR, MET (MET proto-oncogene, receptor tyrosine kinase), and TAM kinases, in combination with the immune checkpoint inhibitor atezolizumab versus regorafenib in patients with non-MSI-H mCRC refractory to standard therapy. Conducted across 121 centers in 16 countries from September 2022 to July 2024, the trial showed a significant overall survival (OS) benefit for zanzalintinib-atezolizumab in the intention-to-treat population (median OS 10.9 months vs 9.4 months; HR 0.80 [95% CI 0.69-0.93]; p=0.0045) and a trend toward improved OS in patients without liver metastases (15.9 months vs 12.7 months; HR 0.79 [95% CI 0.61-1.03]; p=0.087) at a median follow-up of 18.0 months. Grade 3 or worse adverse events were higher with zanzalintinib-atezolizumab (60%) than regorafenib (37%). This study, published in 2025, suggests that zanzalintinib-atezolizumab may enhance TME immunogenicity, potentially offering a chemotherapy-free option for heavily pretreated MSS mCRC patients, although the combination's toxicity profile warrants careful consideration in clinical decision-making. The review's exploration of ICI combinations with chemotherapy, radiotherapy, anti-angiogenics, and MEK (mitogen-activated protein kinase kinase) inhibitors is thorough, but recent trials provide granular insights into optimizing these strategies. For ICI plus targeted therapy, the CAMILLA trial [9] has matured data in 2025, showing a disease control rate (DCR) of 86% in MSS mCRC with cabozantinib and durvalumab. A follow-up analysis revealed that immunogenic cell death correlates with increased neoantigen load, measured via circulating tumor DNA (ctDNA), predicting responders with 85% accuracy. This supplements the review by linking targeted therapy's role to dynamic biomarkers, addressing heterogeneity. Radiotherapy synergies with immunotherapy are being optimized in neoadjuvant settings. The ongoing mRCAT-III phase III trial [10] (NCT06507371) is evaluating a novel regimen of node-sparing modified short-course radiotherapy combined with CAPOX chemotherapy and tislelizumab (a PD-1 inhibitor) versus conventional short-course chemoradiotherapy in patients with proficient mismatch repair or microsatellite stable locally advanced rectal cancer (LARC). This innovative approach is predicated on the hypothesis that excluding tumor-draining lymph nodes (TDLNs) from the irradiation field preserves critical T-cell immunity, which may enhance the efficacy of concurrent PD-1 blockade. Building upon a preceding phase II trial that reported a high pathological complete response (pCR) rate of 78.8%, this phase III study aims to determine whether this node-sparing strategy improves the pCR rate compared with standard short-course chemoradiotherapy. The trial design directly addresses a key challenge in radio-immunotherapy: the conventional irradiation of TDLNs may paradoxically undermine systemic anti-tumor immunity. This aligns with and extends the review's discussion on NACRT [11] combinations by introducing a potentially pivotal technical modification to radiotherapy planning. The primary endpoint is pCR rate, and the trial is currently recruiting patients. Emerging avenues to overcome resistance to immune checkpoint inhibitors (ICIs) include gut microbiota modulation. A 2025 meta-analysis [12] of 10 clinical studies, encompassing 164 patients with advanced solid tumors, provided preliminary evidence that fecal microbiota transplantation (FMT) can enhance the efficacy of ICIs. The pooled analysis demonstrated an objective response rate (ORR) of 43% for the FMT-ICI combination. Notably, the therapeutic benefit appeared more pronounced in patients receiving combined anti-PD-1 and anti-CTLA-4 therapy, who achieved a significantly higher ORR of 60% compared to 37% with anti-PD-1 monotherapy. The safety profile was manageable, with grade 1-2 and grade 3-4 adverse events occurring in 42% and 37% of patients, respectively. This analysis quantitatively substantiates the potential of microbiota-focused strategies discussed in the review's corresponding section, while also underscoring the need for larger randomized controlled trials to validate and refine these findings.Other Immune-Related Therapies: Oncolytic Virotherapy, The review's Section 5 offers a comprehensive overview of oncolytic virotherapy (OV), adoptive cell therapy (ACT), and matrix-depletion therapy, outlining their distinct mechanisms and limitations in colorectal cancer (CRC). Recent advancements from 2024 to 2025 have further developed these approaches, with particular emphasis on their integration with immune checkpoint inhibitors (ICIs) and their application in targeting metastatic sites. For oncolytic virotherapy, recent evidence underscores the dual mechanisms of OVs, involving direct tumor cell lysis and immune activation, where selective replication within CRC cells promotes antigen release and transforms immunologically "cold" tumor microenvironments (TMEs) into "hot" ones [13]. Building upon the review's discussion of Newcastle disease virus-based gene therapy (NDV-GT), a preclinical investigation has demonstrated that adenoviruses engineered to express LIGHT, when combined with anti-CTLA-4, effectively eliminate microsatellite-stable (MSS) liver metastases in murine models by inducing M1 macrophage polarization, augmenting T-cell infiltration, and elevating IFN-γ levels [14]. This finding addresses a critical challenge in managing metastatic disease, consistent with observations from a phase I trial showing sustained OV efficacy in CRC patients, with remissions extending to 313 days through antiviral cytokine-mediated pathways [15]. Additionally, targeting TBK1 has been shown to enhance OV potency by intensifying immunogenic cell death, thereby overcoming chemotherapy resistance in CRC xenograft models [16]. Insights from the 16th International Oncolytic Virus Conference in 2025 highlight the promise of engineered viruses, such as those targeting KRAS mutations, which exhibit preclinical effectiveness in inhibiting CRC progression via adaptive immune responses [17]. Nonetheless, obstacles including delivery inefficiencies and neutralizing antibody development are being mitigated through mesenchymal stem cell (MSC) carriers and combinatorial strategies, as summarized in recent analyses of clinical progress [18]. In ACT, the review highlights CAR-T cell therapy directed against carcinoembryonic antigen (CEA), which achieved a 23-month overall survival (OS) in a phase I trial [19]. Recent innovations in CAR-natural killer (NK) cells, fortified with IL-15, have reported a 50% objective response rate (ORR) in MSS CRC without inducing cytokine release syndrome (CRS) [20]. This advancement extends from studies on intraperitoneal NKG2D CAR-NK cell infusions, which stimulated endogenous CD8+ T-cell responses in advanced CRC cases [21]. Analyses further detail the MHC-independent cytotoxic capabilities of CAR-NK cells, focusing on antigens such as CEA and NKG2D ligands, while offering reduced toxicity profiles relative to CAR-T cells [22]. Current research hotspots encompass locoregional administration for peritoneal metastases, demonstrating notable biological activity in treatment-refractory patients. A systematic review [23] of 32 CAR-NK trials reinforces their broadening scope to solid tumors like CRC, including 12 studies exploring intersections with autoimmunity. Regarding matrix-depletion therapy, setbacks have been noted with pegvorhyaluronidase alfa (PEGPH20) in a phase III trial [24]. However, focal adhesion kinase (FAK) inhibitors are emerging as viable options in stroma-enriched CRC. Investigations reveal FAK's interplay with the BRD4-MYC axis, which suppresses tumor proliferation in stromal subtypes through TME modulation [25]. Phase II results indicate a 33% 6-month progression-free survival (PFS) in desmoplastic CRC, enhancing ICI efficacy by alleviating fibrosis and improving immune cell penetration [26]. Reviews emphasize FAK inhibition's capacity to diminish TGF-β-producing fibroblasts, thereby tackling TME heterogeneity [27]. The review's conclusion effectively underscores the critical need for biomarker-driven personalization to overcome obstacles in colorectal cancer (CRC) immunotherapy. Recent advances in 2024-2025 further illuminate the transformative potential of these strategies, particularly in addressing the distinct challenges posed by mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) and proficient mismatch repair/microsatellite stable (pMMR/MSS) CRC subtypes. These developments highlight the importance of integrating novel therapeutic combinations, advanced diagnostic tools, and multi-omics profiling to enhance treatment efficacy and patient outcomes. A significant advancement in dMMR/MSI-H CRC demonstrates the potential of immunotherapy to redefine treatment paradigms. A 2025 randomized phase II trial [28] showed that neoadjuvant PD-1 blockade alone achieved an 80% rate of surgery avoidance in MSI-H solid tumors, including CRC, with 60% of patients achieving complete responses. These findings suggest that immunotherapy could reduce the reliance on invasive procedures in this subset, offering a pathway toward nonoperative management. The trial's success emphasizes the need for biomarkers to identify patients likely to achieve durable responses, reinforcing the review's call for precision approaches in immunologically responsive tumors. In contrast, pMMR/MSS CRC, which constitutes the majority of cases, remains a formidable challenge due to its immunologically "cold" tumor microenvironment. A phase I/II trial [29] evaluating botensilimab, a next-generation CTLA-4 inhibitor, in combination with balstilimab, a PD-1 inhibitor, reported a 61% disease control rate and a 42% two-year survival rate in refractory MSS CRC patients without liver metastases. This combination marks a significant step toward activating immune responses in otherwise resistant tumors, highlighting the potential of dual checkpoint inhibition to reprogram the TME. These results align with the review's emphasis on combinatorial strategies and underscore the importance of patient selection to maximize therapeutic benefits, particularly in the absence of metastatic liver involvement. Looking ahead, the integration of artificial intelligence (AI) with circulating tumor DNA (ctDNA) analysis represents a promising frontier for monitoring treatment response and detecting resistance. A comprehensive 2025 analysis [30] demonstrated that AI-enhanced ctDNA profiling achieved a 95% sensitivity in predicting immune checkpoint inhibitor (ICI) response in CRC, enabling early detection of resistance mechanisms. This approach facilitates real-time adjustments to therapeutic regimens, addressing the dynamic nature of tumor evolution and supporting personalized treatment plans. Such technological advancements are poised to enhance the precision of immunotherapy by identifying actionable molecular alterations. Further, multi-omics profiling of the TME is reshaping our understanding of CRC's immune landscape. A 2025 study [31] integrating transcriptomics and microbiomics identified distinct prognostic subtypes in CRC, linking specific microbial compositions to immunotherapy response. By delineating immune signatures associated with favorable outcomes, this approach enables tailored therapeutic strategies that account for both tumor and host factors. The study highlights the interplay between gut microbiota and immune activation, suggesting that microbial modulation could enhance immunotherapy efficacy, particularly in MSS tumors. High-definition spatial transcriptomics offers another layer of insight into the cellular dynamics of the CRC TME. A 2025 investigation employed this technique to map immune cell interactions at unprecedented resolution, revealing spatial patterns that predict response to immunotherapy [32] . These findings provide a foundation for designing precision interventions that target specific TME components, such as immunosuppressive stromal cells or effector T-cell populations. By integrating spatial data with other omics approaches, researchers can develop comprehensive models to guide immunotherapy development. Despite these advances, significant challenges remain. The scalability of personalized therapies, such as neoantigen vaccines and multi-omics-driven interventions, is hindered by logistical complexities and high costs. Equitable access to these cutting-edge treatments must be prioritized to ensure broad clinical impact. Additionally, the validation of predictive biomarkers across diverse patient populations is essential to translate these innovations into meaningful survival benefits. Collaborative efforts among researchers, clinicians, and policymakers are critical to addressing these barriers. In conclusion, while Zhang et al. provide a robust foundation for understanding CRC immunotherapy, recent 2024-2025 developments highlight the field's rapid maturation (1). The integration of neoadjuvant strategies, novel checkpoint inhibitors, AI-driven diagnostics, and multi-omics profiling holds immense promise for overcoming resistance and personalizing treatment. Sustained efforts to validate biomarkers and enhance accessibility will be pivotal in realizing the full potential of these advancements, ultimately improving outcomes for CRC patients.