bims-spamet 2026-07-26 papers

iScience. 2026 Jul 17. 29(7): 116595

High resolution spatial profiling of the hematopoietic landscape of the murine lung.

Nicholas J Skvir, Alexandra B Ysasi, Veronica Jarzabek, Anthony K Yeung, Jiaji G Chen, Ruben Dries, George J Murphy.

Our current understanding of blood cell development stems primarily from adult bone marrow and the fetal liver. However, emerging evidence highlights the lung as a previously underappreciated residence for hematopoietic cells. Spatial in situ transcriptomics enables accurate mapping of cell identities and interactions within intact tissue, providing insights not accessible by dissociated single-cell profiling. Here, we present a high-resolution spatial transcriptomic atlas of the healthy adult murine lung, emphasizing the hemato-endothelial landscape. As a case study, we developed a workflow to identify and curate rare, often multinucleated, megakaryocytes, by binning spatial enrichment of canonical markers, expert curation, and correction for segmentation artifacts. We characterized the spatial neighborhoods of megakaryocytes within vascular, stromal, and immune microenvironments. We demonstrate the utility of this dataset for hypothesis-driven signaling studies by examining ligand-receptor interactions across canonical pathways. This resource defines the lung-blood niche and advances our understanding of the organ-specific properties of blood cells.

Keywords: MERFISH; hematopoiesis; megakaryocytes; murine lung; spatial transcriptomics

DOI: https://doi.org/10.1016/j.isci.2026.116595

Front Immunol. 2026 ;17 1878140

Tryptophan metabolism in tumor immune escape: mechanisms, cellular crosstalk, and therapeutic opportunities.

Jingyun Chen, Xin Wang, Meiheng Gong, Yufeng Wang, Tingting Yu.

Tumor immune escape is increasingly recognized as an immunometabolic process shaped not only by immune checkpoints and suppressive cell populations, but also by nutrient competition and metabolic signaling within the tumor microenvironment. This nutrient-competitive environment is not limited to tryptophan depletion, but also involves glucose restriction, glutamine dependence, arginine metabolism, amino acid transporter competition, and impaired mitochondrial fitness of effector T cells. Among amino acid pathways, tryptophan metabolism has emerged as a central regulator of tumor-immune interactions. Through the activity of indoleamine 2, 3-dioxygenase 1 (IDO1), tryptophan 2, 3-dioxygenase (TDO2), kynurenine-producing branches, and both AHR-dependent and AHR-independent downstream programs, tumors establish a metabolic state that couples tryptophan depletion, metabolite signaling, redox adaptation, and immune suppression. Recent evidence further shows that tryptophan metabolism is not restricted to tumor cells, but also involves cancer-associated fibroblasts, macrophages, and T cells, thereby shaping multicellular crosstalk within immunosuppressive niches. Beyond immune suppression, this pathway contributes to ferroptosis resistance, stemness, metastatic adaptation, and resistance to chemotherapy, targeted therapy, and immune checkpoint blockade. In parallel, circulating metabolites and tissue-level metabolic profiling are being explored as potential biomarkers for patient stratification and treatment response prediction. In this review, we summarize the molecular basis of tryptophan catabolism in cancer, discuss its role in tumor-immune-stromal communication, and highlight emerging translational and therapeutic opportunities. Rather than reviewing tryptophan metabolism as a linear IDO1/TDO2-centered pathway, we define it as a multicellular immunometabolic communication network in which tumor cells, stromal fibroblasts, myeloid cells, and lymphocytes exchange metabolic and signaling cues to create spatially organized immunosuppressive niches. This network-based view helps explain why single-enzyme inhibition is often insufficient and supports the development of biomarker-guided, multi-branch, and cell-context-specific therapeutic strategies.

Keywords: immunometabolism; kynurenine; tryptophan metabolism; tumor immune escape; tumor microenvironment

DOI: https://doi.org/10.3389/fimmu.2026.1878140

Anal Bioanal Chem. 2026 Jul 23.

Towards spatial lipid profiling by using mass spectrometry: analytical challenges and applications.

Yaowei Liu, Yihua Ou, Hemi Luan, Tiangang Luan.

Lipidomics, as a crucial branch of metabolomics, is dedicated to systematically analyzing the composition, structure, function, and dynamic changes of lipids in organisms, playing a pivotal role in elucidating disease mechanisms and discovering biomarkers. Conventional lipidomics methods based on liquid chromatography-mass spectrometry (LC-MS) require tissue homogenization, which obscures the spatial distribution of lipids and precludes the analysis of their heterogeneity within complex tissue microenvironments. In recent years, the development of spatial omics technologies such as mass spectrometry imaging (MSI) and laser capture microdissection (LCM) has provided powerful tools for the in situ and visual investigation of lipid spatial distribution. This paper systematically reviews the main analytical strategies in lipidomics, focusing on the technical principles, advances, and recent applications of spatial multi-omics integration. It further discusses the challenges faced by spatial lipidomics in terms of quantitative accuracy, isomer identification, and spatial localization precision, and provides an outlook on future technological developments. Spatial lipidomics breaks through the bottleneck of losing spatial information in traditional methods, and opens up a new path for further exploration of disease mechanisms and the discovery of new biomarkers in the spatial dimension.

Keywords: Laser capture microdissection; Lipid metabolism; Mass spectrometry imaging; Spatial lipidomics; Spatial multi-omics

DOI: https://doi.org/10.1007/s00216-026-06684-y

Mol Oncol. 2026 Jul 23.

Spatial biology in cancer epigenetics.

Eva Crespo-García, Manel Esteller.

Cancer develops inside organized tissue environments wherein cellular behavior is heavily influenced by local interactions and spatially restricted regulatory programs. While bulk and single-cell sequencing technologies have fundamentally revolutionized our understanding of tumor biology, these techniques often disrupt tissue architecture and therefore fail to capture the spatial context in which molecular processes occur. Spatial transcriptomics has provided important insights into tumor heterogeneity, microenvironmental organization, and cell-to-cell communication. However, gene expression alone offers only an indirect view of the regulatory mechanisms governing cellular states. The emergence of spatial epigenomic technologies now enables the investigation of chromatin accessibility, histone modifications, and DNA methylation while preserving tissue structure. Here, we discuss the current landscape of spatial epigenomics, including spatial ATAC-seq, spatial CUT&Tag, emerging spatial CUT&RUN approaches, spatial DNA methylation profiling, and multimodal strategies integrating epigenetic, transcriptional, and proteomic information within the same tissue context. Despite remaining technical and computational challenges, continued advances are expected to establish spatial epigenomics as a powerful tool for studying cancer pathways and their regulation within intact tissues.

Keywords: DNA methylation; cancer; chromatin; epigenetics; histone modifications; spatial biology

DOI: https://doi.org/10.1002/1878-0261.70310

Nat Biotechnol. 2026 Jul 22.

Single-nucleus multimodal spatial transcriptomics reveals spatial colocalization of neoantigen-expressing tumor cells and cognate T cells.

Improved methods to identify therapeutically relevant tumor neoantigens and their cognate T cells would aid the development of precision medicines for cancer. Here, we developed Slide-GoTags, a droplet-based single-nucleus spatial transcriptomics approach that characterizes neoantigen-specific immunity by integrating targeted transcript genotyping and T cell receptor (TCR) sequencing with single-nucleus RNA sequencing from the same slice of frozen tissue. Application of Slide-GoTags to mouse and human tumors revealed colocalization of clonally expanded, neoantigen-specific T cells with tumor cells expressing their cognate neoantigen. We also identified distinct spatial immune landscapes shaped by anti-PD1 or anti-CTLA4 blockade in mouse colorectal tumors. Across human tumor types, Slide-GoTags detected TCR-neoantigen interactions through spatial proximity and identified an enrichment of interferon-driven immunogenicity niches in immunologically 'hot' tumors compared to 'cold' tumors. These niches harbored three T cell clonotypes that colocalized with genotyped neoantigens, highlighting a spatially organized antitumor immune response. Collectively, Slide-GoTags establishes a framework for in situ mapping of T cell-tumor interactions directly from individual tissue.

DOI: https://doi.org/10.1038/s41587-026-03194-1

iScience. 2026 Jul 17. 29(7): 116544

Immune-epithelial crosstalk governs immune checkpoint inhibitor efficacy in colorectal cancer.

Sheah Lin Lee, Adrian C Bateman, Margaret Ashton-Key, John N Primrose, Alex Mirnezami, Aymen Al-Shamkhani, Stephen M Thirdborough.

Colorectal cancer (CRC) with deficient DNA mismatch repair (dMMR) elicits a CD8+ T cell response. However, the magnitude and composition of this response vary among patients, influencing the efficacy of immune checkpoint inhibitors (ICIs). To investigate this heterogeneity, we integrated bulk transcriptomics with immune repertoire sequencing in dMMR CRC. We identified co-regulated gene modules associated with T- and B cell clonal expansion, immune-metabolic interactions, and therapeutic response. Key transcriptional programs linked to T cell clonality and ICI responsiveness were validated using spatial transcriptomics and the TCGA-CRC cohort. We observed an inverse relationship between immune activation and oxidative metabolism and identified immune-epithelial crosstalk as a determinant of ICI efficacy. These findings may inform biomarker development and patient stratification in both dMMR and mismatch repair-proficient CRC. Transcriptional programs linked to T cell clonality in dMMR CRC also define a subset of immunologically active microsatellite-stable tumors, supporting the rationale for extending ICI-based therapies to these patients.

Keywords: T and B cell clonality; checkpoint inhibitor; immune-epithelial crosstalk; mismatch repair-deficient colorectal cancer; spatial transcriptomics

DOI: https://doi.org/10.1016/j.isci.2026.116544