To evaluate whether adding tumor microenvironment markers

The gap

Evidence profile

Sourced from the future-work section and future work of the source papers, classified as general, spanning 3 journals.

Supporting evidence — 3 representative gaps

• Letter to the Editor: Integrating immune-related metrics with personalize first-line immunochemotherapy in human epidermal growth factor receptor 2-negative advanced gastric cancer (2026) · World Journal of Gastrointestinal Oncology · doi

  To evaluate whether adding tumor microenvironment markers improves discrimination and reclassification over the current model. To develop modular, updateable prognostic platforms that permit incremental incorporation of tissue and circulating biomarkers. To prioritize external validation across independent, multi-center cohorts treated with different PD-1 agents and chemotherapy regimens.

  generalfuture-work section
  Keywords: evaluate whether adding tumor microenvironment markers improves discrimination
• 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 workevidence 5/5
  Keywords: clinical escc immunotherapy treatment advanced combination regimens novel biomarkers lack tumor resistance signaling cacy second
• Impact of metastatic pattern and histologic subtype on PD-(L)1 inhibitor efficacy in HER2-negative advanced gastric and gastroesophageal cancer: a meta-analysis (2026) · Frontiers in Oncology · doi

  Future research should focus on integrating spatial and single- cell immune profiling to elucidate mechanisms of resistance to immune checkpoint inhibition in peritoneal and diffuse-type dis- ease. Evaluating mechanism-driven combination regimens, includ- ing PD-(L)1 inhibitors paired with anti-fibrotic, anti-VEGF, or anti- TGF-b agents, as well as locoregional therapies like HIPEC or PIPAC may help remodel immune-TME and enhance therapeutic response. Several of these strategies are currently under investiga- tion in preclinical models or early-phase trials in GC, including intraperitoneal chemotherapy combined with immune checkpoint inhibitor (22–24, 27). In parallel, prospective, biomarker-driven clinical trials stratified by histologic subtype and metastatic pattern are warranted to validate subgroup-specific therapeutic strategies. Finally, the incorporation of immune gene expression signatures could enable real-time monitoring of treatment response and resistance evolution.

  generalfuture workevidence 5/5
  Keywords: immune anti resistance checkpoint driven therapeutic response strategies trials future focus integrating spatial single cell

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