Search Results (151)

Microsatellite instability-high (MSI-H) and deficient mismatch repair (dMMR) define a molecular subtype of colorectal cancer (CRC) and predict benefit from immune checkpoint inhibition. Clinically, MSI/MMR assessment may yield discordant results across assays, anatomic sites, or time points. A challenging scenario occurs when tissue analysis identifies microsatellite-stable (MSS) or mismatch repair-proficient (pMMR) CRC, whereas circulating tumor DNA (ctDNA) analysis indicates MSI-H. This review evaluates evidence for MSI/MMR heterogeneity and subclonality in CRC. We reviewed literature on spatial, temporal and subclonal MSI/MMR heterogeneity across human cancers, focusing on CRC. Explanations for tissue–plasma and tissue–tissue discordance, including assay limitations, sampling bias, lesions misattribution, biological evolution, and treatment-related selection, were assessed. Although discordance more commonly reflects assay limitations, sampling bias, or profiling of different lesions, increasing evidence supports genuine biological heterogeneity. Distinct tumor regions may show retained MMR protein expression in one area and regional loss with MSI in another. Noncanonical MMR defects, epigenetic heterogeneity, post-treatment evolution, adaptive mutator-state, and immune selection may also generate dynamic or subclonal instability. Therapeutic relevance may depend not simply on MSI detection, but on whether the unstable clone is sufficiently dominant to generate broadly shared neoantigens across the disease burden. MSI/MMR discordance requires careful interpretation and should not automatically be considered as true biological heterogeneity. Nevertheless, genuine subclonality occurs in CRC and other cancers and may affect responsiveness to immune checkpoint inhibition. Integrated tissue, plasma, spatial and longitudinal analyses may improve treatment decisions and biomarker development. Full article

Colorectal cancer (CRC) has shown significant heterogeneity regarding its response to immunotherapy. Long-lasting, beneficial effects have been observed in mismatch repair-deficient, microsatellite instability-high (dMMR/MSI-H) tumours, while mismatch repair-proficient, microsatellite stable (pMMR/MSS) tumours have remained resistant. Such differences in results have been studied in this review through the “hot” and “cold” tumour concept. It explains how various biological and microenvironmental factors play a role in immune resistance and T-cell priming and infiltration. Key factors include a low neoantigen load and defects in antigen presentation, which reduce the overall immune recognition of tumour cells. The review also studies certain processes such as Wnt/β-catenin and mitogen-activated protein kinase (MAPK) signalling and what input they have in the prevention of effective antitumour immune responses. Conventional treatments like chemotherapy and radiotherapy have been considered alongside more targeted treatments such as the inhibition of vascular endothelial growth factor (VEGF) signalling and the suppression of myeloid-mediated immune evasion, to convert “cold” MSS tumours into immune-responsive lesions. Methods which aim to modify the tumour microenvironment such as metabolic reprogramming and microbiome modulation have also been covered in this review. Artificial intelligence and nanomedicine are new technologies that could provide improved patient stratification and therapeutic precision, although their clinical application in pMMR/MSS CRC remains under investigation. A systematic literature search of PubMed and PubMed Central (PMC) was conducted from 10 June 2026 to 19 August 2026 using predefined eligibility criteria, with study selection reported according to PRISMA 2020. Because of substantial heterogeneity in study design, therapeutic approach and reported outcomes, the included evidence was synthesized narratively rather than by meta-analysis. A total of 158 studies were included. Full article

Colorectal cancer (CRC) remains a major cause of cancer morbidity and mortality. Immune checkpoint inhibitors (ICIs) have transformed the treatment of microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) CRC, yet most CRCs are microsatellite-stable/mismatch repair-proficient (MSS/pMMR) and remain poorly responsive to immunotherapy. MicroRNAs (miRNAs) are well positioned to influence this biology because individual miRNAs can coordinate multiple tumor-intrinsic and microenvironmental programs that shape antitumor immunity. Rather than cataloging miRNAs one by one, this review organizes the evidence around the major barriers that sustain an immune-cold CRC microenvironment: altered checkpoint and costimulatory signaling, defective antigen presentation, impaired effector T-cell access and function, suppressive myeloid and stromal compartments, and extracellular vesicle (EV)-mediated intercellular communication. We also critically assess tissue and circulating miRNA signatures as candidate biomarkers of ICI response and discuss therapeutic approaches based on miRNA mimics, inhibitors, and targeted delivery platforms. The available evidence supports a biologically compelling role for miRNA networks in CRC immune regulation, but clinical translation remains limited by context dependence, delivery, off-target effects, and the lack of treatment-linked validation in CRC cohorts. Full article

Immune checkpoint blockade has become an important component of treatment for several gynecologic malignancies, but its clinical value varies substantially by tumor lineage, molecular subtype, disease setting, and treatment backbone. This narrative review summarizes the biological rationale, clinical evidence, predictive biomarkers, combination strategies, toxicity considerations, and future directions of immunotherapy across gynecologic cancers. In cervical cancer, checkpoint blockade has evolved from later-line recurrent disease to first-line systemic therapy and, more recently, to curative-intent chemoradiotherapy combinations. In endometrial cancer, mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) tumors show the clearest sensitivity to programmed cell death protein 1 (PD-1) blockade, whereas mismatch repair-proficient/microsatellite stable (pMMR/MSS) disease generally requires combination strategies. In ovarian cancer, broad unselected checkpoint inhibitor strategies have generally failed; ENGOT-ov65/KEYNOTE-B96 demonstrated statistically significant progression-free survival (PFS) and overall survival (OS) improvement with pembrolizumab plus weekly paclitaxel, with or without bevacizumab, in a defined platinum-resistant population, although the absolute median PFS gain in PD-L1 combined positive score (CPS) ≥1 disease was modest. Gestational trophoblastic neoplasia (GTN) offers a biologically distinctive setting because of trophoblastic immune tolerance, whereas selected rare gynecologic malignancies may be considered for immunotherapy on the basis of HPV association, tumor-agnostic biomarkers, or signals observed in clear-cell cohorts. Accordingly, the clinical value of immunotherapy should be interpreted according to tumor lineage, disease setting, validated biomarkers, treatment backbone, and the incremental contribution of each treatment component. Full article

Perioperative treatment for colorectal cancer (CRC) is undergoing a paradigm shift from uniform cytotoxic regimens toward strategies guided by tumor location, microsatellite instability (MSI)/mismatch repair (MMR) status, and recurrence risk. Four clinically relevant subgroups now shape decision-making: microsatellite stable (MSS)/proficient MMR (pMMR) colon cancer, microsatellite instability-high (MSI-H)/deficient MMR (dMMR) colon cancer, MSS/pMMR rectal cancer, and MSI-H/dMMR rectal cancer. In MSS/pMMR colon cancer, adjuvant therapy is being refined through risk-adapted treatment duration and selective use of neoadjuvant chemotherapy. In MSS/pMMR rectal cancer, total neoadjuvant therapy, selective omission of pelvic radiotherapy, and watch-and-wait strategies are redefining treatment sequencing and organ preservation. In MSI-H/dMMR colon cancer, immune checkpoint inhibitor (ICI) therapy has shown marked activity in both adjuvant and neoadjuvant settings. In MSI-H/dMMR rectal cancer, neoadjuvant ICI therapy is being explored as a non-operative organ preservation strategy. In parallel, circulating tumor DNA (ctDNA)-based minimal residual disease (MRD) assessment is emerging as a tool for postoperative escalation, de-escalation, and surveillance. Across these settings, the maturity of the evidence varies widely, ranging from established phase III standards to guideline-endorsed but still single-arm approaches and investigational strategies that require prospective validation before routine adoption. This review summarizes the current evidence and remaining challenges in biology-, site-, and risk-adapted perioperative management of CRC. Full article

Immune checkpoint inhibitors (ICIs) have significantly changed the treatment landscape of several gastrointestinal (GI) malignancies, particularly microsatellite instability-high (MSI-H) and mismatch repair-deficient (dMMR) tumors. However, most GI cancers remain resistant to current PD-1/PD-L1-based immunotherapy because of complex and highly suppressive tumor microenvironments characterized by immune stromal exclusion, myeloid-driven immune suppression, defective antigen presentation, and adaptive immune resistance mechanisms. Emerging evidence suggests that alternative inhibitory pathways, including lymphocyte activation gene-3 (LAG-3), T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), and V-domain Ig suppressor of T-cell activation (VISTA), contribute substantially to persistent T-cell dysfunction and resistance to checkpoint blockade. This review summarizes the immune landscape of GI malignancies and discusses the biological mechanisms underlying resistance to current ICIs. We highlight the evolving role of next-generation immune checkpoints, ongoing clinical development of novel inhibitors, and emerging combination strategies involving chemotherapy, anti-angiogenic therapy, radiation, bispecific antibodies, and tumor microenvironment modulation. In addition, we discuss current limitations in biomarker development and the growing role of circulating tumor DNA, spatial immune profiling, and multi-omics approaches in patient selection. Finally, we explore future directions aimed at improving precision immunotherapy and expanding durable responses across GI cancers. Full article

Background/Objectives: Deficient mismatch repair (dMMR) and microsatellite instability-high (MSI-H) colorectal cancer (CRC) are highly sensitive to immune checkpoint blockade. We evaluated the efficacy, safety, and clinical maturity of neoadjuvant PD-1-based immunotherapy in localized disease. Methods: This PRISMA-compliant systematic review included prospective studies of neoadjuvant PD-1-based therapy in localized dMMR/MSI-H CRC. Proportions were pooled on the logit scale using inverse-variance random-effects models with the Paule–Mandel estimator. Pathologic complete response (pCR) was the primary outcome; major pathologic response (MPR), immune-related adverse events (irAEs), surgery, clinical complete response (cCR), organ preservation, and long-term outcomes were secondary outcomes. Results: Five prospective studies were included. Four studies, comprising 305 treated patients and 292 pathologically evaluable patients, contributed five treatment arms to the quantitative synthesis. The pooled pCR proportion was 0.65 (95% CI, 0.54–0.74), and the pooled MPR proportion was 0.89 (95% CI, 0.79–0.94). Exploratory subgroup analyses suggested higher response proportions with combination regimens, but clinical and methodological differences confounded these predominantly indirect comparisons. Any-grade irAEs occurred in 0.54 (95% CI, 0.36–0.71), whereas grade ≥3 irAEs occurred in 0.06 (95% CI, 0.04–0.10). The pooled surgery proportion was 0.96 (95% CI, 0.86–0.99), although this outcome largely reflected protocol-mandated surgery. cCR and organ preservation were promising in selected rectal-cancer cohorts. Survival and recurrence data were immature and unsuitable for quantitative pooling. Conclusions: Neoadjuvant PD-1-based immunotherapy is a highly promising investigational strategy for localized dMMR/MSI-H CRC. Nevertheless, predominantly early-phase evidence, indirect comparisons, heterogeneous endpoints, and limited follow-up preclude definitive conclusions regarding routine clinical adoption. Full article

The 27th annual Western Canadian Gastrointestinal Cancer Consensus Conference (WCGCCC) was held in Calgary, Alberta, on 26–27 September 2025. The WCGCCC is an interactive multidisciplinary conference that was attended by healthcare professionals from across Western Canada (British Columbia, Alberta, Saskatchewan, and Manitoba) who are involved in the care of patients with colorectal cancer. Specialists from the fields of medical and radiation oncology, pathology, surgery, and a family physician in oncology participated in presentations and discussions for the purpose of developing the recommendations presented here. This consensus statement addresses recent advances in the management of colorectal cancer in a Western Canadian context, with respect to adjuvant exercise, as per the CHALLENGE trial, adjuvant Aspirin and PI3K testing, as per the ALASCCA trial, adjuvant immunotherapy, as per the ATOMIC trial, the use of encorafenib and an EGFR inhibitor with chemotherapy, as per the BREAKWATER trial, the use of combination immunotherapy as per the CHECKMATE 8HW trial and optimal strategies for omitting radiation and non-operative management of non-metastatic rectal cancer. Full article

Early-onset colorectal cancer is increasing, making reproductive health an increasingly relevant survivorship issue. While immune checkpoint inhibitors have altered the management of deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) colorectal cancer, their implications for reproductive-age women remain insufficiently defined. We performed a focused narrative review, structured in line with the SANRA framework, to clarify this specific clinical domain. Immunotherapy may reshape female oncofertility counseling through two distinct mechanisms: direct reproductive uncertainty, including established endocrine toxicities and hypothesized, but currently unproven, direct gonadal effects; and indirect pathway-modifying effects, such as the potential avoidance of pelvic radiotherapy or radical surgery in selected patients with locally advanced dMMR/MSI-H rectal cancer. Anatomical organ preservation should not be automatically equated with functional fertility preservation. The key clinical message is that reproductive counseling should not be restricted to historically gonadotoxic chemotherapy. Instead, early multidisciplinary guidance should explicitly distinguish CRC-specific evidence from extrapolated or theoretical concerns, integrate fertility preservation strategies when clinically feasible, and address pelvic and sexual health, contraception, washout, endocrine follow-up, and future pregnancy planning. Until prospective CRC-specific reproductive data become available, immunotherapy should not be presented as either reproductively neutral or fertility-preserving. Full article

Pancreatic cancer remains one of the most aggressive and lethal malignancies, characterized by late-stage diagnosis, profound molecular heterogeneity, and limited responsiveness to conventional cytotoxic therapies. Recent advances in molecular diagnostics and biomarker-driven treatment stratification have accelerated the development of precision therapeutic approaches aimed at improving outcomes in selected patient populations. This review highlights three mechanistically distinct yet complementary therapeutic strategies that illustrate the evolving landscape of personalized pancreatic cancer management. Adagrasib represents targeted inhibition of oncogenic KRAS G12C signaling, reflecting recent progress in directly targeting historically “undruggable” driver mutations. Dostarlimab illustrates the tissue-agnostic application of immune checkpoint blockade in pancreatic cancers harboring mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H), highlighting the growing importance of biomarker-defined immunotherapy-responsive subsets despite the limited pancreatic cancer-specific clinical evidence currently available. Trastuzumab deruxtecan represents a next-generation HER2-directed antibody–drug conjugate (ADC) and demonstrates the potential of HER2-targeted therapy in the small subgroup of patients with HER2-positive pancreatic cancer, although the available evidence is derived primarily from basket trials and tumor-agnostic clinical development. Collectively, these therapeutic approaches underscore the expanding role of biomarker-guided treatment strategies integrating targeted inhibition, immunotherapy, and precision cytotoxic payload delivery. This review summarizes the molecular rationale, available clinical evidence, therapeutic limitations, and resistance mechanisms associated with these approaches while discussing emerging directions in translational research, rational combination strategies, liquid biopsy applications, and precision oncology that may further refine individualized treatment algorithms for pancreatic cancer. Full article

Background: Endometrial carcinoma (EC) is one of the most common gynaecological malignancies, with a steadily increasing incidence worldwide. In 2013, a novel molecular classification of ECs enabled patient stratification into four groups with important clinical management implications: (1) DNA Polymerase Epsilon (POLE)-mutated, (2) microsatellite instability-high (MSI-H/dMMR) hypermutated, (3) tumours with low somatic copy number alteration (low-SCNA), and (4) tumours with high SCNA and p53 deficiency. This molecular classification should also be used as a tool to identify hereditary cancer syndromes, as MSI-ECs can be associated with Lynch Syndrome (LS, ORPHA:144) while somatic POLE mutations may reflect polymerase proofreading-associated polyposis (PPAP syndrome, ORPHA:447877). Methods: From 2022 to 2024, molecular classification of ECs was routinely performed on 188 consecutive cases. The results were correlated with family history and constitutional genetic testing. Results: Somatic testing revealed that 45 ECs were dMMR and 23 carried POLE variants. Five POLE-mutated ECs also displayed concomitant MSI. For all 68 patients, cancer genetic counselling was proposed, but only 41 accepted, and of these, 26 patients were eligible for the genetic test. None of the POLE somatic variants were proven to be constitutive, whereas LS was diagnosed in seven patients with dMMR-EC; interestingly, two of these patients displayed a POLE-mutated EC. Conclusions: Our data strongly suggest that molecular classification of ECs is important to improve the identification of LS and highlight the relevance of investigating all molecular markers at once in order to identify overlaps between POLE mutations and MMR defects. Full article

Colorectal cancer (CRC) exhibits a highly heterogeneous tumor immune microenvironment (TME), ranging from “immune-inflamed” to “immune-desert” or “immune-excluded” phenotypes. Understanding how immune cell composition, cytolytic activity (CYT) and genomic alternations shape tumor-immune interactions is critical for improving immunotherapy outcomes. We analyzed TCGA-COAD and TCGA-READ datasets to evaluate immune competency, CYT, immune subtypes, microsatellite instability (MSI), and genomic instability, including somatic mutations, copy number aberrations (CNAs), and chromothriptic events. Immune cell infiltration was correlated with CYT levels, immune checkpoint expression, and immune-related gene signatures. Immune-competent (IC) tumors were predominantly CYT-high, enriched in stromal and immune scores, and exhibited distinct TME characteristics compared with immune-deficient (ID) tumors. IC/CYT-high tumors expressed higher levels of immune checkpoints (PD-1, PD-L1, CTLA-4, IDO1/2, LAG-3) and cytokines/chemokines (C1QA/B/C, CXCL9/10/11, CXCL13). Differences in immune infiltration were observed across tumors with significant mutations and copy number alterations. No prognostic difference was observed between CYT-high and CYT-low patients, indicating that CYT reflects immune activation rather than clinical outcome. Functionally, stimulated CD8⁺ T cells exhibited cytotoxicity activity against MSI-high (HCT-116) and microsatellite-stable (HT-29) CRC cells, with MSI-H cells showing higher sensitivity. Dynamic 3D co-culture demonstrated tumor-guided T cell infiltration and retention of CD8 expression, and co-culture was associated with moderate upregulation of cytotoxicity-related genes GZMA and PRF1 within the system. Cytotoxic activity decreased at lower effector-to-target ratios, highlighting the importance of effector dose. Overall, these findings link CYT, immune competency, MSI status, and genomic instability to T cell cytotoxic responses, providing insights into tumor-immune interactions, and suggest potential associations relevant for immunotherapy research in CRC. Full article

Mismatch repair–deficient (dMMR) or microsatellite instability-high (MSI-H) colorectal cancers exhibit high mutational burden and abundant neoantigen formation, generating a highly immunogenic tumour microenvironment characterised by dense lymphocytic infiltration and strong sensitivity to immune checkpoint inhibition. In metastatic colorectal cancer, PD-1 blockade produces durable responses almost exclusively in dMMR tumours, establishing mismatch repair status as a predictive biomarker for immunotherapy responsiveness. Recent studies extending immune checkpoint inhibitors (ICIs) into the neoadjuvant setting for localised dMMR colorectal cancer have produced major pathological response rates exceeding 90%, with pathological complete response (pCR) rates frequently surpassing 60%, challenging traditional oncologic staging frameworks, particularly with respect to lymph node assessment. Baseline clinical nodal staging in dMMR tumours is complicated by immune-mediated lymphadenopathy. Reactive lymphoid hyperplasia driven by tumour antigen exposure frequently produces enlarged lymph nodes that mimic metastatic disease on cross-sectional imaging. Following neoadjuvant immunotherapy, treatment-related immune activation may further increase nodal size or metabolic activity, while pathological examination often reveals sterilised nodes or immune infiltration without viable tumour. Consequently, conventional radiologic criteria for nodal metastasis demonstrate limited specificity in this context. The discordance between imaging findings and pathological outcomes raises important implications for staging accuracy, response assessment, and treatment planning. This review examines the biological basis of lymphatic involvement in dMMR colorectal cancer, evaluates the performance of current imaging modalities for nodal staging, and summarises emerging evidence from neoadjuvant immunotherapy trials. Particular emphasis is placed on the interpretation of lymph node findings in the era of immune checkpoint blockade and the implications for surgical decision-making, organ preservation, and future staging paradigms. Full article

Background: Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, with poor survival rates of late-stage disease. While immune checkpoint blockade (ICB) therapy has transformed treatment for mismatch repair-deficient (MMRd)/microsatellite instability-high (MSI-H) tumors, most CRC cases are mismatch repair-proficient (MMRp)/microsatellite-stable (MSS) and derive little to no benefit from current immunotherapy regimens. Tumor-associated macrophages (TAMs) constitute a significant component of the tumor microenvironment (TME) and exhibit a phenotypic gradient between pro-inflammatory (M1-like) and anti-inflammatory, immunosuppressive (M2-like) states. Although their polarization status is increasingly recognized as a key modulator of immunotherapy efficacy in CRC, a comprehensive synthesis of the literature regarding macrophage polarization and its relevance to improving CRC immunotherapy remains lacking. Methods: A systematic literature search was conducted across PubMed, EMBASE, and ScienceDirect from inception to December 2025 using terms encompassing macrophages, immunotherapy, immune checkpoint expression, colorectal cancer, and microsatellite stability status. Title, abstract, and full-text screening were performed independently by multiple authors. Sixty-five studies were included following PRISMA guidelines. The protocol was prospectively registered on PROSPERO (ID: CRD420251244320). Results: Three key themes were identified: (1) macrophage-mediated mechanisms of resistance to ICB, including M2 polarization driven by the PI3Kγ, STAT3, mTOR, and SIRT-1 axes, immunosuppressive cytokine production (IL-10, TGF-β), and altered immune checkpoint ligand expression; (2) macrophage polarization status and associated biomarkers as prognostic indicators of therapeutic response; (3) emerging macrophage-targeted therapeutic strategies in ongoing clinical trials, including CSF1R inhibitors, CD40 agonists, CD47/SIRPα blockade, and STING agonists. Conclusions: TAM polarization is a critical determinant of immunotherapy resistance and patient prognosis in CRC. Macrophage-targeted strategies, particularly M2-to-M1 repolarization approaches used in combination with existing ICB regimens, represent a promising avenue for expanding immunotherapy efficacy beyond MSI-H disease. Further translational research and randomized controlled trials are needed to validate these targets clinically. Full article

The therapeutic armamentarium for colorectal cancer (CRC) has been significantly expanded with the introduction of immunotherapy, particularly immune checkpoint inhibitors (ICIs). However, the response to immunotherapy is strongly dependent on microsatellite instability (MSI) status. Tumors with high MSI (MSI-H) and/or mismatch repair deficiency (dMMR) exhibit high tumor mutational burden (TMB), increased neoantigen load, and enhanced immunogenicity, leading to improved responses to ICIs compared with microsatellite-stable (MSS) and/or mismatch repair-proficient (pMMR) tumors. This has changed the treatment landscape of this small subgroup of metastatic CRC (mCRC), including the approval of pembrolizumab as a first-line option. In contrast, most mCRC cases are MSS/pMMR and are resistant or poorly responsive to ICIs, with no established standard immunotherapy strategy. Therefore, current approaches aim to convert these “cold” tumors into “hot,” immunologically active tumors. This review summarizes the distinct molecular basis of MSI phenotypes and their interaction with the tumor microenvironment, and provides relevant insights into current clinical evidence for prognostic and predictive biomarkers beyond MSI status, as well as novel therapeutic strategies to overcome resistance in MSS disease. Full article