Aug 2026· Oncology Report· Vol 56· 0 citations· 176 references
Medicine
TL;DR
Focusing on acquired resistance as a core bottleneck in precision therapy, mechanisms underlying anti-Human Epidermal Growth Factor Receptor 2 (HER2) resistance and primary/secondary resistance to immune checkpoint inhibitors (ICIs) were systematically dissected, while also addressing immune-related adverse events and pseudo-/hyperprogression.
Abstract
The emergence of molecular classifications for gastric cancer (GC), The Cancer Genome Atlas (TCGA) and Asian Cancer Research Group (ACRG), has advanced targeted and immunotherapies, but their clinical translation faces real-world obstacles including high cost, tissue availability, standardization, and intratumoral heterogeneity. The present review critically compares the two classification systems regarding prognostic utility across geographic populations and boundary conflicts, noting that ACRG is more operable in East Asian populations whereas TCGA is better suited for mechanistic exploration. Focusing on acquired resistance as a core bottleneck in precision therapy, mechanisms underlying anti-Human Epidermal Growth Factor Receptor 2 (HER2) resistance and primary/secondary resistance to immune checkpoint inhibitors (ICIs) were systematically dissected, while also addressing immune-related adverse events and pseudo-/hyperprogression. Moreover, non-immune elements of the tumor microenvironment deserve attention: Cancer-associated fibroblasts limit drug penetration and promote epithelial-mesenchymal transition through physical barriers and paracrine signaling; metabolic reprogramming (high glycolysis and glutamine addiction) impairs chemotherapy and ICI efficacy via an acidic microenvironment and metabolic competition. Finally, multi-target combination strategies are envisioned based on pathway redundancy, along with liquid biopsy-driven dynamic adaptive therapy and single-cell/spatial multi-omics integration for precise microenvironment intervention. The present review aims to offer a systematic reference for moving GC precision therapy from static subtyping toward dynamic, multi-dimensional integration.
Key oncogenic signaling pathways, including PI3K/AKT/mTOR and RAS/RAF/MEK/ERK, were discussed in the context of therapeutic targeting and precision medicine and emerging strategies, particularly immunotherapy and combination approaches were addressed.
Xin-Yu Li, Jie Liu, Fang-Fang Huang et al.· Oncology Letters· 0 citations
This review synthesizes current data on cellular, molecular, and systemic predictors, focusing on immune cell phenotypes, protein biomarkers, gene signatures, and metabolic factors, focusing on immune cell phenotypes, protein biomarkers, gene signatures, and metabolic factors.
E.A. Tsarenkova, A. Kalinchuk, E. Shmakova et al.· Clinical and Translational O...· 0 citations
Ovarian cancer is the most lethal gynecologic malignancy, primarily because of late-stage diagnosis, rapid disease progression, and marked molecular and immunologic heterogeneity. It remains the leading cause of gynecologic cancer-related death, affecting approximately 1 in 70 women in developed countries over their lifetimes. Tumor development and progression are orchestrated within the tumor immune microenvironment, a dynamic and complex structural niche that supports malignant transformation and immune evasion of the tumor. In this narrative educational review, we aim to provide a comprehensive overview of recent advances in the understanding of ovarian cancer pathogenesis, the molecular mechanisms driving tumor progression, and the multifaceted role of the immune system in disease development and therapeutic response. Moreover, we summarize recent clinical trials targeting key molecular drivers and components of the tumor immune microenvironment, including immunotherapeutic and targeted approaches. Personalized medicine, guided by integrative genomic and transcriptomic profiling, has become increasingly vital for patient stratification and treatment selection. Ultimately, a shift toward highly individualized, mechanism-based therapeutic strategies is essential to improve clinical outcomes and survival in ovarian cancer.
B. Vavrušáková, R. Bartošová, M. Hendrych et al.· Discover Oncology· 0 citations
Breast cancer is a leading cause of cancer -related morbidity and mortality, characterized by significant biological and molecular heterogeneity. Molecular subtypes —including luminal A, luminal B, HER2 - enriched, and triple -negative—inform prognosis and guide prec ision therapies. Despite advances with endocrine agents, HER2-targeted therapies, PARP inhibitors, and immune checkpoint inhibitors, therapeutic resistance remains a major challenge, driven by intratumoral heterogeneity, cancer stem cell plasticity, and tumor microenvironmental factors. Genomic profiling, liquid biopsies, combination and adaptive strategies, and next-generation antibody-drug conjugates are emerging to overcome resistance and optimize outcomes. Additionally, novel immunotherapies and artific ial intelligence (AI) –assisted decision -making support individualized treatment selection. This review summarizes recent advances, from molecular characterization to precision-guided interventions and strategies to counteract resistance, and emphasizes the integration of biological insights into personalized breast cancer management.
Immunotherapy has reshaped the treatment landscape of colorectal cancer (CRC), with the clearest and most durable benefit established in mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) disease. However, framing CRC immunotherapy simply as "MSI-H responsive versus microsatellite stable (MSS) resistant" is no longer sufficient. Recent studies indicate that a subset of proficient mismatch repair (pMMR) colon cancers, particularly in the neoadjuvant setting, can mount clinically meaningful responses to immune checkpoint blockade, suggesting that disease stage, local immune organization, and treatment timing critically influence immunotherapy sensitivity. In parallel, emerging evidence has expanded the relevant immune landscape beyond the tumor bed itself, showing that spatially organized stromal and adipose niches can actively divert tumor-reactive lymphocytes and promote immune escape. These advances shift the central challenge in CRC immunotherapy from simply identifying new agents to defining when and in whom immune resistance is reversible, and which biological bottlenecks-such as vascular dysfunction, myeloid suppression, and spatial immune exclusion-must be overcome. In this context, alternative checkpoint inhibitors, bispecific antibodies, cellular therapies, vaccines, nanotechnology-enabled platforms, and microbiome-targeted approaches remain important, but their translational maturity and evidentiary support differ substantially. Biomarker development is likewise evolving from static genomic classification toward dynamic and mechanism-informed stratification incorporating circulating tumor DNA (ctDNA), chromosomal instability, immune architecture, and treatment-induced response trajectories. This review synthesizes recent advances in CRC immunotherapy while emphasizing evidence hierarchy, biomarker-guided patient selection, and the mechanistic basis of combination strategies. We argue that the next phase of CRC immunotherapy will depend less on the indiscriminate addition of novel agents and more on the rational deployment of immunotherapy across molecularly, spatially, and temporally defined disease states.
: Advanced gastroesophageal adenocarcinomas (GEA) have undergone a major therapeutic shift from empiric chemotherapy toward biomarker-driven precision oncology. Routine incorporation of immunohistochemistry (IHC), in situ hybridization, next-generation sequencing (NGS), and liquid biopsy have enabled identification of actionable subgroups that now guide first-line and subsequent treatment selection. Four biomarkers have established clinical utility in current practice: mismatch repair deficiency (dMMR)/microsatellite instability-high (MSI-H) status, human epidermal growth factor receptor 2 (HER2) amplification or overexpression, programmed death ligand 1 (PD-L1) expression, and claudin 18.2 (CLDN18.2). MSI-H/dMMR represents the strongest predictor of durable benefit from immune checkpoint inhibition across treatment lines. HER2-positive disease has evolved beyond trastuzumab-based therapy with the emergence of antibody–drug conjugates and bispecific antibodies that are redefining outcomes. PD-L1 combined positive score (CPS) remains most impactful in selecting patients for first-line chemo-immunotherapy, while its predictive role beyond first line is less consistent. Most recently, CLDN18.2 targeting has expanded therapeutic options in HER2-negative disease, with zolbetuximab establishing a new first-line standard and multiple antibody drug conjugate strategies emerging. This review aims to summarize the current evidence supporting biomarker-driven treatment strategies in advanced GEA, highlight practical biomarker testing considerations, and discuss ongoing challenges and future directions in precision oncology.
Fares Jamal, Abdullah Alsulaiman, Oudai Sahwan et al.· Oncology Research· 0 citations
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