CXCL12 (C-X-C Motif Chemokine Ligand 12)

Pharmacological antagonism of CXCL12/CXCR4 axis potentiated the immunotherapy efficacy in orthotopic TNBC mouse models. In conclusion, this study highlights a HTRA1+ macrophage subpopulation that can limit T cell infiltration and immunotherapy efficacy via the CXCL12/CXCR4 axis, which offers new leads to improve immunotherapeutic interventions in TNBC.

Epigenetic programs govern leukemia's dependence on stromal support, inflammatory and niche-derived signals, as well as the microenvironment signaling pathways. Overall, targeting leukemia-niche interactions is a crucial strategy for improving outcomes in ALL and to identify potential molecular vulnerabilities, also for developing new therapeutic approaches for the treatment of the disease.

DIC exerts its core antitumor effects by targeting DKK1 to inhibit Wnt/β-catenin signaling and EMT. Additionally, it independently suppresses angiogenesis and remodels the immune tumor microenvironment. This multi-level mechanism positions DIC as a promising lead compound for prostate cancer therapy.

Collectively, these findings highlight the critical role of CAF heterogeneity and spatial organization in modulating the response to anti-PD-1 therapy. Targeting subtype-specific stromal modules may represent a promising therapeutic strategy to enhance the efficacy of immunotherapy in breast cancer.

Enhancing pericyte maturity or intercepting transitions toward CAFs are promising avenues to boost treatment efficacy. We propose a practical framework for classifying "MSC-pericyte states" in the TME and emphasize rigorous, multi-marker, spatially resolved analyses to dissect their complex functions, thus opening a new scenario for targeted therapies.

Emerging therapeutic strategies aim to disrupt this axis by depleting Tregs (e.g., anti-CD25), blocking MDSC recruitment (e.g., CCR2 inhibitors), or reprogramming TAMs (e.g., CD40 agonists), often in combination with programmed death 1/programmed death-ligand 1 blockade. An integrated approach targeting these populations holds promise for converting pancreatic ductal adenocarcinoma into an immunologically responsive tumor.

Building on these insights, this review also argues for subtype-specific biomarkers and multimodal therapeutic strategies to overcome stromal-mediated resistance. Integrating stromal heterogeneity into precision-oncology workflows through standardized, lineage-resolved profiling and real-time biomarker guidance will be essential for diagnostic refinement and personalized treatment.

Additionally, immune cell infiltration analysis using CIBERSORT revealed a higher proportion of macrophages in both cancer types compared to non-tumor tissues. In conclusion, our study suggests that shared genetic alterations, regulated by specific TFs and miRNAs, alongside an altered immune microenvironment and CXCL12-mediated inositol phosphate metabolism likely driven by intermediate monocytes, contribute to the development of SPLC following laryngeal cancer.

The immunophenotypic changes in the expression profile of several markers under the influence of SP may indicate the induction of the epithelial-mesenchymal transition in the MCF-7 cells and increased migration activity in both cell lines.

Finally, a LightGBM model predicted danger zone scores directly from H&E slides, correlating with stromal infiltration and patient survival. This study defines the danger zone as a key spatial feature of GC progression and immunosuppression, offering novel biomarkers, prognostic tools, and therapeutic targets.

Consistently, NE-conditioned KCs enhanced colorectal cancer cell migration via CXCL12, an effect that was attenuated by pharmacological inhibition of β2-AR signaling or blockade of the CXCL12-CXCR4 axis. Overall, this study identifies a norepinephrine-driven neuroimmune mechanism in which β2-AR signaling reprograms KCs toward a pro-metastatic phenotype, thereby facilitating CRLM.

While further validation is needed, our findings indicate that multifocal SI-NETs consist of spatially distinct tumor cell subtypes affected by local cellular interactions, providing insight into SI-NET intra-tumoral heterogeneity, possible microenvironmental-triggered tumorigenesis, and potential subtype-targeted therapeutic strategies.