DMMR/MSI-H tumors represent a population with clear benefit from immunotherapy, this subtype is not biologically homogeneous

The gap

Evidence profile

Sourced from the future work of the source papers, classified as general, drawn from work published between 2025 and 2026, spanning 3 journals. Those papers have been cited 9 times in total.

Supporting evidence — 3 representative gaps

• Advances and challenges in immunotherapy for advanced esophageal squamous cell carcinoma (2026) · Frontiers in Immunology · doi

  The advent of immunotherapy has profoundly reshaped the treatment landscape for advanced ESCC. From second-line to first- line settings, and from monotherapy to combination regimens, immunotherapeutic strategies centered on PD-1/PD-L1 inhibitors have established their standard position, delivering durable survival benefits for patients. Concurrently, pioneering explorations into novel combination strategies (e.g., with anti-angiogenic agents, TIGIT inhibitors), BsAbs, and CAR-T cell therapies offer potential for further improving treatment outcomes. Despite the progress made in immunotherapy for advanced ESCC, several core challenges in clinical practice demand urgent solutions. First, the predictive value of biomarkers remains limited. PD-L1 testing suffers from inconsistencies across scoring systems, detection platforms, and cut-off values. Biomarkers like TMB and MSI have constrained applicability in ESCC. Novel multi-omics biomarkers and liquid biopsy technologies are still in the exploratory clinical phase, hindered by small sample sizes, lack of assay standardization, tumor spatiotemporal heterogeneity, and impeding their integration into clinical decision- high costs, making frameworks. Second, the mechanisms of immune resistance are complex and not yet fully elucidated. Intrinsic tumor factors such as neoantigen deficiency, aberrant signaling pathways, and epigenetic alterations, along with extrinsic factors mediated by the TME including immunosuppression, metabolic reprogramming, and abnormal angiogenesis, collectively contribute to primary or acquired resistance, posing a key barrier to enhancing immunotherapy efficacy. Third, the therapeutic needs of special populations remain inadequately addressed. Elderly and frail patients are underrepresented in clinical studies, leading to a lack of dedicated treatment regimens and safety data, making it difficult to accurately assess their benefit-risk profile in clinical application. Fourth, obstacles persist in the clinical translation of novel immunotherapies. Modalities like BsAbs and CAR-T therapies have yet to demonstrate significant “enhanced efficacy with reduced toxicity” advantages in ESCC, and some combination regimens lack confirmatory Phase III data to support their efficacy. Future advancements in immunotherapy for advanced ESCC will pivot around the core directions of precision, personalization, and diversification, focusing on overcoming the following research FIGURE 2 (A) Interference with MHC-I, TAP, and b2M expression leading to loss of tumor neoantigens; (B) Aberrant activation and mutation of oncogenic signaling pathways affecting cell signaling, PD-L1 resistance, and immunosuppression; (C) Epigenetic alterations (involving DNA methylation and histone modification) resulting in reduced chemokine production and increased VEGFC expression.

  generalfuture work
  Keywords: clinical escc immunotherapy treatment advanced combination regimens novel biomarkers lack tumor resistance signaling cacy second
• Current Treatment Options Guided by Molecular Classification in Endometrial Cancer (2026) · Current Treatment Options in Oncology · doi

  Although dMMR/MSI-H tumors represent a population with clear benefit from immunotherapy, this subtype is not biologically homogeneous. Further studies are needed to clarify how different etiological backgrounds, immune microenvironment features, and resistance mechanisms influence treatment efficacy. Whether mismatch repair sta- tus should be routinely reassessed after recurrence or metas- tasis remains dependent on the clinical context. However, reassessment may have clinical value when test results are equivocal, when post-treatment specimens are evaluated, or when subclonal loss is suspected. Beyond the PD-1/pro- grammed death ligand 1 (PD-L1) axis, strategies targeting lymphocyte activation gene 3 (LAG-3), T-cell immuno- globulin and mucin-domain containing 3 (TIM-3), and dual immune checkpoint blockade may provide new avenues for patients with primary or acquired resistance to PD-1 inhibi- tors, although current evidence is insufficient to change 1 3Current Treatment Options in Oncology(2026)27:44 clinical practice. Therefore, future precision treatment for dMMR/MSI-H endometrial cancer should move beyond confirming dMMR status alone and toward identifying dis- tinct etiological backgrounds, resistance mechanisms, and recurrence risks, thereby optimizing combination, mainte- nance, and retreatment strategies [12]. POLE-Mutated Tumors: Favorable Prognosis and Treatment De-Escalation

  generalfuture work
  Keywords: treatment dmmr resistance clinical tumors etiological backgrounds immune mechanisms recurrence beyond strategies current represent population
• Tumour- and Non-Tumour-Associated Factors That Modulate Response to PD-1/PD-L1 Inhibitors in Non-Small Cell Lung Cancer (2025) · Cancers · cited 9× · doi

  PD-1/PD-L1 inhibitors have had a profound impact on the management and treatment of NSCLC patients. This has reinvigorated the interest of researchers and oncologists in the tumour microenvironment, which was often overlooked in the past. High PD-L1 expression, high tumour mutation burden, and microsatellite instability are the most robust predictive biomarkers for the response to PD-1/PD-L1 checkpoint therapy. This review addresses both tumour-associated and non-tumour-associated biomarkers that may predict the response to PD-1/PD-L1 blockade in NSCLC patients (Figure 4). It is important to note that all the potential biomarkers mentioned above do not act in isolation to improve or impair the anti-tumour response, but instead, they work in tandem within the tumour immune microenvironment and even influence each other, often contributing to a pro-tumour or anti-tumour response. Personalizing treatment regimens based on the status of multiple biomarkers will provide further avenues to improve patient responses. Evidence from recent studies emphasizes the value of profiling STK11 and KEAP1 mutations to personalize ICI treatment. Future approaches should therefore consider combining STK11/KEAP1 mutation status, TMB, PD-L1 expression, and microbiome profiling to identify patients who are most likely to benefit from monotherapy vs. combination treatments and to guide interventions, such as microbiota modulation alongside immunotherapy. Figure 4. Tumour-associated and non-tumour-associated factors that confer response to ICIs in NSCLC. Notably, high-dimensional analyses, including single-cell RNAseq, imaging mass cytom- etry, and spatial transcriptomics, have revealed spatial niches of T cells and macrophages that correlate with survival in lung tumours, suggesting potential biomarkers for immunother- apy response prediction [217]. In parallel, integrating spatial architecture mapping with Cancers 2025, 17, 2199 19 of 30 genomic profiling in early-stage lung cancer has identified distinct TME archetypes associated with differential clinical outcomes and likely differing sensitivities to immunotherapy [218]. These studies exemplify how emerging spatial and multi-omics technologies may potentially improve patient stratification to guide the selection of immunotherapies. However, more research is warranted to identify how a non-immunogenic TME can be transformed into an immunogenic TME. Both chemotherapeutic agents and radiation have been shown to improve tumour immunogenicity by increasing immune cell infiltration, DNA damage response, tumour mutation burden, upregulating PD-L1, and the cytokine response. Multiple clinical trials have shown favourable responses in NSCLC patients with ICI and chemotherapy combinations; however, further studies are required to understand the mechanisms of the enhanced response. In conclusion, further research is needed to refine the currently existing biomarkers and to develop new ones for evaluating the patient response. Author Contributions: Conceptualization, M.K. and M.-S.T.; writing—original draft preparation, M.K.; writing—review and editing, M.K. and M.-S.T.; visualization, M.K.; supervision, M.-S.T.; project administration, M.-S.T.; funding acquisition, M.-S.T. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by the Canadian Institute of Health Research (CIHR) Foundation grant stream (FDN-148395) to M.-S.T. and the CIHR Canada Graduate Scholarship (Doctoral) to M.K. Acknowledgments: All figures are created in BioRender [219]. Conflicts of Interest: Dr. Tsao reports receiving grants from AZ and Sanofi; and personal fees from Daichii-Sankyo, AstraZeneca, Boehringer-Ingelheim, Abbvie, Sanofi, Pfizer and Diaceutics. M.K. declares no conflicts of interest.

  generalfuture work
  Keywords: tumour response biomarkers associated nsclc patients improve spatial treatment interest high mutation further patient profiling

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