Cancer Res. 2026 Feb 9. doi: 10.1158/0008-5472.CAN-25-2854. Online ahead of print.

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) patients with diabetes mellitus (DM) exhibit poor clinical outcomes. Metabolic reprogramming of both cancer cells and immune compartments plays a crucial role in shaping the anti-tumor immune response in PDAC. DM-induced metabolic alteration may disrupt the intricate crosstalk between immune cells and tumor-associated immune factors, profoundly influencing PDAC progression. Here, we performed an integrated, spatially resolved multi-omics study to investigate DM-associated, cell-specific metabolic remodeling within the PDAC tumor microenvironment. DM influenced interactions between tumor cells and immune cells, which accelerated PDAC growth in both humans and mice. PDAC patients with DM exhibited higher tumor-stage, poorer differentiation, and worse outcomes. Spatial metabolic and transcriptional profiling revealed that SREBP2-dependent cholesterol biosynthesis exacerbated PDAC progression. Increased cholesterol biosynthesis promoted neutrophil recruitment and accelerated formation of neutrophil extracellular traps (NETs) by stimulating the CXCL1-CXCR1/CXCR2 signaling axis, ultimately promoting PDAC growth. Inhibition of SREBP2, pharmacological blockade of CXCL1, or perturbation of NETs markedly reduced PDAC growth in diabetic mouse models. Together, these multi-omics analyses and follow-up mechanistic studies constitute an integrated approach that elucidates a metabolic mechanism by which diabetes promotes PDAC development by remodeling the tumor immune microenvironment and highlights a potential therapeutic strategy for PDAC with DM.

PMID:41661642 | DOI:10.1158/0008-5472.CAN-25-2854

Signal Transduct Target Ther. 2025 Jun 15;10(1):186. doi: 10.1038/s41392-025-02243-6.

ABSTRACT

Over the past two decades, non-small cell lung cancer (NSCLC) has witnessed encouraging advancements in basic and clinical research. However, substantial unmet needs remain for patients worldwide, as drug resistance persists as an inevitable reality. Meanwhile, the journey towards amplifying the breadth and depth of the therapeutic effect requires comprehending and integrating diverse and profound progress. In this review, therefore, we aim to comprehensively present such progress that spans the various aspects of molecular pathology, encompassing elucidations of metastatic mechanisms, identification of therapeutic targets, and dissection of spatial omics. Additionally, we also highlight the numerous small molecule and antibody drugs, encompassing their application alone or in combination, across later-line, frontline, neoadjuvant or adjuvant settings. Then, we elaborate on drug resistance mechanisms, mainly involving targeted therapies and immunotherapies, revealed by our proposed theoretical models to clarify interactions between cancer cells and a variety of non-malignant cells, as well as almost all the biological regulatory pathways. Finally, we outline mechanistic perspectives to pursue innovative treatments of NSCLC, through leveraging artificial intelligence to incorporate the latest insights into the design of finely-tuned, biomarker-driven combination strategies. This review not only provides an overview of the various strategies of how to reshape available armamentarium, but also illustrates an example of clinical translation of how to develop novel targeted drugs, to revolutionize therapeutic landscape for NSCLC.

PMID:40517166 | PMC:PMC12167388 | DOI:10.1038/s41392-025-02243-6