Immune checkpoint inhibitors have changed the treatment landscape for gastric and gastroesophageal junction adenocarcinoma, yet durable benefit remains uneven across biomarker-defined groups. PD-L1 combined positive score, MSI/dMMR, tumor mutational burden, EBV status, HER2, and CLDN18.2 guide treatment eligibility, but they do not explain why effector immunity succeeds in one lesion and fails in another. This narrative review uses spatial immune niches as a framework for interpreting immunotherapy resistance in gastric cancer. These niches are tissue compartments in which malignant-cell states, effector-cell access, tertiary lymphoid structures, cancer-associated fibroblasts, tumor-associated macrophages, extracellular matrix, vascular function, and metastatic-site ecology jointly shape response. We synthesize evidence from clinical trials, single-cell and spatial multi-omics, multiplex immunohistochemistry and immunofluorescence, digital pathology, and translational biomarker studies. The review highlights clinically relevant niche states, including lymphoid-organized inflamed, inflamed-but-suppressed, stromal-excluded, myeloid-dominant, vascular/hypoxic, target-antigen-associated, and peritoneal metastatic niches. It further discusses how compact spatial assays could refine patient selection and support niche-matched combination strategies.

Resistance to tyrosine kinase inhibitors (TKIs) severely limits their long-term efficacy in renal cell carcinoma (RCC). Here, we identify prolyl 4-hydroxylase subunit alpha 3 (P4HA3) as a critical driver of TKI resistance and elucidate its underlying mechanism. P4HA3 was markedly upregulated in TKI-resistant RCC cells, and its overexpression promoted proliferation and resistance to sunitinib and axitinib, whereas P4HA3 depletion restored drug sensitivity and suppressed tumor growth in vitro and in vivo. Mechanistically, P4HA3 inhibited ferroptosis by stabilizing the cystine transporter SLC7A11, thereby maintaining redox homeostasis and suppressing lipid peroxidation. P4HA3 directly interacted with SLC7A11 and induced hydroxyproline modification at residues P153 and P161, which attenuated NEDD4-mediated ubiquitination and proteasomal degradation of SLC7A11. Moreover, a hydroxylase-inactive P4HA3 mutant failed to stabilize SLC7A11, suppress ferroptosis, or promote TKI resistance, demonstrating the essential role of P4HA3 enzymatic activity. Importantly, pharmacological inhibition of P4HA3 using Tubuloside A or 1,4-DPCA disrupted the P4HA3-SLC7A11 axis and significantly enhanced TKI efficacy across RCC cell lines, patient-derived organoids, and xenograft models. Together, these findings establish a hydroxylation-dependent P4HA3-SLC7A11-NEDD4 axis that drives ferroptosis evasion and TKI resistance in RCC and highlight P4HA3 as a promising therapeutic target.

This narrative review aimed to critically synthesize and evaluate the current evidence on the roles of TIR domain-containing adaptor protein in tumorigenesis and cancer progression, with a particular focus on elucidating the underlying inflammatory and immune regulatory mechanisms mediated by toll-like receptor signaling. A targeted literature search of recent studies (2015-2024) was performed using PubMed and Web of Science. Classic foundational publications (1998-2014) were supplemented through reference tracking. We included experimental, cellular, and clinical studies focusing on TIR domain-containing adaptor protein in cancer. The synthesized findings indicate that TIR domain-containing adaptor protein has been implicated in malignant progression in bladder, pancreatic, and gastric cancers by sustaining chronic inflammation and shaping an immunosuppressive tumor microenvironment through the TLR2/4-MyD88-NF-κB/MAPK axis, whereas it may exert homeostatic and protective effects in colorectal cancer. TIR domain-containing adaptor protein activity is tightly regulated by cellular origin, ligand specificity, and epigenetic modifications such as promoter methylation, which are closely associated with cancer risk and disease severity. TIR domain-containing adaptor protein serves as a critical regulator in inflammation-driven tumors with distinct context-dependent functions and represents a promising biomarker and therapeutic target. Further research focusing on its precise regulatory mechanisms and cell-specific targeted strategies will facilitate its clinical translation.

Coagulation factor VII (F7) has been implicated in tumor progression; however, its role in gastric cancer metastasis and immune evasion remains incompletely understood. In this study, we identified F7 as a clinically relevant driver of gastric cancer. F7 was highly expressed in tumor tissues and closely associated with lymph node metastasis, poor prognosis, and reduced CD8+ T-cell infiltration. Tumor-derived autocrine F7 interacted with ITGA2 on the cancer cell surface and activated ITGA2-associated FAK-NF-κB signaling and promoted invasion, migration, and anoikis resistance. F7 induced PD-L1 expression in a manner partly dependent on ITGA2-mediated PI3K-AKT signaling and promoted collagen I deposition in liver metastatic lesions, which was associated with reduced CD8+ T-cell infiltration. Co-immunoprecipitation showed that the K1.2 and K1.3 regions of F7 mediated its interaction with the N-terminal extracellular region of ITGA2. Further investigations identified HNF4A as an upstream transcription factor of F7, with anoikis-associated stress enhancing HNF4A nuclear accumulation and F7 transcription. Notably, ThonningianinA (THA) was identified as a potential F7-targeting small molecule that suppressed F7-associated malignant phenotypes, reduced tumor growth, and enhanced the antitumor efficacy of anti-PD-1 therapy. These findings support F7 as a potential therapeutic target for metastatic gastric cancer.

The imaging arsenal for nuclear medicine physicians continues to grow rapidly with multiple radiopharmaceuticals now being used routinely in clinical practice. More specifically, PET imaging targeting various aspects of tumor biology has demonstrated utility in diagnosing incidental/synchronous malignancies as well as biochemical profiling of tumors for prognostication (ie, in the setting of prostate and neuro-endocrine cancers). These concepts are illustrated in this case of an incidental gastric gastrointestinal stromal tumor (GIST) which was imaged with 3 separate PET radiopharmaceuticals.

Krukenberg tumors are an uncommon metastatic malignancy most commonly originating primarily from the gastrointestinal tract, particularly the stomach, colon, and/or rectum. Due to the rarity of these malignancies, most patients are believed to have primary metastatic ovarian malignancy instead. Here, we present the case of a patient who was presumed to have ovarian metastatic cancer; however, pathology results showed that the malignancy was gastrointestinal primary in nature. In this instance, intraoperative findings and immunohistochemical profiling played a crucial role in differentiating a Krukenberg tumor with a gastrointestinal primary versus ovarian metastatic cancer. In this case, proper diagnosis resulted in a change of management, highlighting that even the most unlikely differentials should still be considered.

Immunotherapy holds promise for gastric cancer, but its efficacy is constrained by primary and acquired resistance. Resistance mechanisms are complex, stemming from tumor features-such as the tumor microenvironment (TME). The TME is a dynamic ecosystem where tumor-immune-stromal interactions shape antitumor responses. Existing prognostic markers have clinical value, yet their insufficiency reflects the multidimensional nature of tumor-immune crosstalk. Emerging evidence indicates that immunotherapy response is a systems-level phenomenon. This review synthesizes current data on cellular, molecular, and systemic predictors, focusing on immune cell phenotypes, protein biomarkers, gene signatures, and metabolic factors. Integrative models capturing the functional state of the TME consistently outperform single biomarkers. Nevertheless, significant challenges remain, including a lack of standardization, limited prospective validation, and TME temporal plasticity, which complicates static biomarker assessments. Ultimately, predicting response requires understanding the tumor-immune ecosystem as an integrated, dynamic system to improve patient stratification and outcomes.

Gastrointestinal cancers encompass a range of malignancies, including esophageal, gastric, esophagogastric, hepatocellular, pancreatic, and intestinal cancers. Considering the prevalence of these cancers, alongside their fatal nature, and the nonspecific symptoms that often arise in the advanced stages, developing a non-invasive screening/diagnostic method capable of detecting cancer early is in high demand. Exhaled breath serves as an accessible source of biomarkers, including volatile organic compounds (VOCs), a promising type of diagnostic marker. This method requires a sample as small as five breaths. Exhaled breath analysis is conducted using different mass spectrometry methods coupled with nano sensors or neural networks. Furthermore, innovative devices like electronic noses have also shown great promise in diagnosing different types of cancers. These biomarkers show potential in reliably differentiating between healthy individuals and cancer patients. Additionally, these compounds can be utilized for cancer staging and monitoring treatment response. However, certain fallbacks persist in differentiating malignant from pre-malignant conditions. Despite the promise of this diagnostic approach, certain limitations, such as variations in VOC profiles across different populations, lack of standardized collection protocols, and absence of established universal reference standards, underscore the need for proper standardization and large-scale, multi-center validation studies.