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BackgroundPancreatic cancer (PC) remains largely refractory to immune checkpoint inhibitors (ICIs), especially in the prevalent microsatellite-stable (MSS) subtype. However, combination strategies of ICIs with chemotherapy have largely failed in MSS PC, highlighting an urgent need for novel immunotherapeutic approaches. Cadonilimab is a novel programmed death protein 1(PD-1)/cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) bispecific antibody designed to remodel the immunosuppressive tumor microenvironment.Case report descriptionWe report an exceptional and durable response to cadonilimab plus chemotherapy in a patient with metastatic MSS pancreatic cystadenocarcinoma (PCAC). Microsatellite stability was shown by immunohistochemistry with intact expression of all four mismatch repair proteins (MLH1, MSH2, MSH6, PMS2) and confirmed by next-generation sequencing (NGS). Following disease progression on first-line gemcitabine/nab-paclitaxel and transarterial chemoembolization (TACE), the patient subsequently received second-line therapy with cadonilimab combined with nab-paclitaxel and oxaliplatin. Notably, within two months of treatment initiation, the patient achieved near-complete remission (near-CR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria, with an 89.9% reduction in the sum of target lesion diameters. Despite discontinuing anticancer therapy after 4 cycles due to grade 3 bone marrow suppression, which subsequently evolved into and has been maintained as a complete response (CR) for over 30 months, with the primary endpoint of progression-free survival (PFS) not yet reached.ConclusionThis case provides pioneering clinical evidence that cadonilimab, in combination with chemotherapy, can induce profound and durable remission in MSS PCAC, challenging current paradigms of ICI resistance and supporting the further development of bispecific antibody strategies.

The use of immune checkpoint inhibitors (ICIs) has revolutionized cancer care, particularly in immune-inflamed tumors and tumors with a high mutational burden, like microsatellite instable colorectal cancer (CRC). However, their effectiveness in microsatellite stable (MSS) CRC is limited. This systematic review aims to evaluate the efficacy of ICIs in MSS CRC and explore promising combination strategies. A comprehensive search from the Web of Science, Medline, and Embase databases, for studies published until 14 November 2022, identified 53 clinical trials included in the review. ICI monotherapy or ICI-ICI combinations demonstrated limited clinical activity for patients with MSS CRC, with overall response rates below (ORR) 10% in most studies. The ICI and tyrosine kinase inhibitor (TKI) garnered ORRs ranging from 10% to 40% and indicated a higher benefit for patients, particularly those without active liver metastases. The combination of ICIs with anti-VEGF agents showed modest ORRs, especially in the earlier treatment lines and in combination with chemotherapy. While these combinations could lead to modest improvements, well-defined biomarkers for long-term benefit are yet to be delineated. Combinations involving BRAF inhibitors with ICIs were studied, showing promising responses with combination approaches in molecularly defined subgroups. In conclusion, while ICI monotherapy has limited efficacy in MSS CRC, combination strategies hold promise to enhance survival outcomes. Further research is necessary to identify optimal combination approaches, predictive biomarkers for treatment response, as well as enrollment according to tumor molecular characteristics. This review evaluates the efficacy of immune checkpoint inhibitors in ICIs in microsatellite stable colorectal cancer and explores promising combination strategies.

CRC is the third most diagnosed cancer in the US with the second-highest mortality rate. A multi-modality approach with surgery/chemotherapy is used in patients with early stages of colon cancer. Radiation therapy is added to the armamentarium in patients with locally advanced rectal cancer. While some patients with metastatic CRC are cured, the majority remain incurable and receive palliative chemotherapy as the standard of care. Recently, immune checkpoint blockade has emerged as a promising treatment for many solid tumors, including CRC with microsatellite instability. However, it has not been effective for microsatellite stable CRC. Here, main mechanisms of immunosuppression in CRC will be discussed, aiming to provide some insights for restoring immunosurveillance to improve treatment efficacy in CRC.

To explore the immune microenvironment of RAS ‐mutated ( RAS mt) microsatellite stable (MSS) colon cancer (CC), we retrospectively performed whole exome sequencing, RNA sequencing, and robust digital pathology analyses and studied immune markers in a cohort of 161 patients treated with standard‐of‐care therapies with early stage disease (both fresh frozen and formalin‐fixed paraffin‐embedded [FFPE] samples) or 121 patients with metastatic setting (primary tumor FFPE samples). Only a small proportion of cases exhibited a highly infiltrated immune microenvironment, with a strong association between Immunoscore ® (IS)‐high (13% of the samples) and Tumor Lymphocytes Infiltrating Score (TuLIS)‐high scores (25% of the samples). Immunoscore Immune‐Checkpoint (ISIC)‐high tumors (52% of the samples) shared a similar microenvironment composition to IS‐high and TuLIS‐like high tumors and displayed higher mutational burdens than ISIC‐low tumors. In conclusion, a substantial proportion of MSS RAS mt CCs exhibit high ISIC scores, meriting evaluation in prospective trials of immunotherapy‐based combination regimens.

Colorectal cancer (CRC) remains a significant cause of cancer-related mortality worldwide. Despite advancements in surgery, chemotherapy, and radiotherapy, the effectiveness of these conventional treatments is limited, particularly in advanced cases. Therefore, transition to novel treatment is urgently needed. Immunotherapy, especially immune checkpoint inhibitors (ICIs), has shown promise in improving outcomes for CRC patients. Notably, patients with deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) tumors often benefit from ICIs, while the majority of CRC cases, which exhibit proficient mismatch repair (pMMR) or microsatellite-stable (MSS) status, generally show resistance to this approach. It is assumed that the MSI phenotype cause some changes in the tumor microenvironment (TME), thus triggering antitumor immunity and leading to response to immunotherapy. Understanding these differences in the TME relative to MSI status is essential for developing more effective therapeutic strategies. This review provides an overview of the TME components in CRC and explores current approaches aimed at enhancing ICI efficacy in MSS CRC.

In recent years, deepening knowledge of the complex interactions between the immune system and cancer cells has led to the advent of effective immunotherapies that have revolutionized the therapeutic paradigm of several cancer types. However, colorectal cancer (CRC) is one of the tumor types in which immunotherapy has proven less effective. While there is solid clinical evidence for the therapeutic role of immune checkpoint inhibitors in mismatch repair-deficient (dMMR) and in highly microsatellite instable (MSI-H) metastatic CRC (mCRC), blockade of CTLA-4 or PD-L1/PD-1 as monotherapy has not conferred any major clinical benefit to patients with MMR-proficient (pMMR) or microsatellite stable (MSS) mCRC, reflecting 95% of the CRC population. There thus remains a high unmet medical need for the development of novel immunotherapy approaches for the vast majority of patients with pMMR or MSS/MSI-low (MSI-L) mCRC. Defining the molecular mechanisms for immunogenicity in mCRC and mediating immune resistance in MSS mCRC is needed to develop predictive biomarkers and effective therapeutic combination strategies. Here we review available clinical data from combinatorial therapeutic approaches using immunotherapy-based strategies for MSS mCRC.

Abstract BRAFV600E-mutant metastatic colorectal cancer (mCRC) is an aggressive molecular subtype associated with poor prognosis and relative chemoresistance. Outcomes following progression on chemotherapy and MAPK-targeted therapy with encorafenib plus cetuximab remain poor, highlighting an unmet need for effective later-line treatments. Immune checkpoint inhibitors have limited activity in microsatellite-stable (MSS) mCRC, and predictive biomarkers beyond mismatch repair deficiency remain poorly defined. We report a patient with BRAFV600E-mutant MSS mCRC who achieved a prolonged response to PD-1 blockade with pembrolizumab following a dynamic increase in tumor mutational burden (TMB). A 58-year-old woman initially responded to first-line chemotherapy but subsequently progressed on multiple treatment lines, including encorafenib plus cetuximab. Longitudinal genomic profiling using tumor tissue and circulating tumor DNA (ctDNA) revealed persistent BRAFV600E signaling with molecular evolution, including acquisition of a PIK3R1 variant associated with resistance to MAPK inhibition and emergence of TMB-high status. Fifth-line pembrolizumab produced a dramatic radiological response, with ongoing disease control more than 2 years later. We discuss the mechanistic framework by which a subset of BRAFV600E-mutant MSS mCRC may respond to immune checkpoint inhibition through an inflamed immune microenvironment driven by constitutive MAPK signaling. This case illustrates the interplay between tumor-agnostic biomarkers such as TMB-high and tumor-specific context, and highlights the value of longitudinal genomic profiling, including ctDNA, to identify resistance mechanisms and guide treatment selection.

Tertiary lymphoid structures (TLSs) are ectopic lymphoid aggregates located at sites of chronic inflammation and recognized as prognosticators in several cancers. We aimed to analyse the prognostic effect of TLSs in colorectal cancer (CRC) pulmonary metastases and primary tumours, with a comparison to the CD3+ and CD8+ cell density-based immune cell score (ICS). For TLS density and TLS maximum diameter analysis, 67 pulmonary metastases and 63 primary tumours were stained with haematoxylin and eosin. For ICS scoring and analysis, CD3 and CD8 immunohistochemistry was performed. Excellent interobserver agreement was achieved in all TLS measurements. Of all patients, 36 patients had low TLS density (< 0.222 follicles/mm) and 31 patients had high TLS density (≥ 0.222 follicles/mm) in the first resected pulmonary metastases. TLS density (adjusted HR 0.91, 0.48–1.73) or maximum diameter (adjusted HR 0.78, 0.40–1.51) did not have prognostic value in pulmonary metastases. In primary tumours, higher TLS density (adjusted HR 0.39, 0.18–0.87) and maximum diameter (adjusted HR 0.28, 0.11–0.73) were associated with lower mortality. In the pulmonary metastases, ICS had superior prognostic value to TLSs; however, TLSs and ICS were significantly associated. In conclusion, TLSs in CRC pulmonary metastases had no prognostic value but correlated with the ICS. TLSs in primary tumours associated with favourable prognosis.

Colorectal cancer (CRC), particularly the immunologically “cold” microsatellite-stable (MSS) subtype, remains profoundly resistant to immune checkpoint inhibitors. Antibody-drug conjugates (ADCs) are rapidly emerging as a transformative therapeutic modality poised to overcome this challenge. This review reframes ADCs beyond their role as targeted cytotoxics, repositioning them as sophisticated immuno-oncology agents. The central thesis is that by strategically selecting payloads such as topoisomerase inhibitors or auristatins, modern ADCs can induce immunogenic cell death (ICD) or pyroptosis. This mechanism effectively functions as an in situ vaccine, transforming the tumor microenvironment from “cold” to “hot” by promoting dendritic cell activation and T-cell infiltration. We provide a comprehensive overview of the ADC landscape, examining key targets on bulk tumor cells (CEACAM5, HER2), cancer stem cells (LGR5, GPR56), and stromal components. We conclude that the future of ADCs in CRC lies in their rational application as immune-priming agents, creating powerful synergies in combination with checkpoint inhibitors to break therapeutic resistance and durably improve patient outcomes.