Jul 2026· Journal of Translational Medicine· 0 citations
Medicine
TL;DR
How myeloid programs and neutrophil extracellular trap formation, cancer-associated fibroblast subsets and extracellular matrix barriers, aberrant vasculature and hypoxia-linked metabolism, and the tumor-nerve signaling axis cooperatively shape immunosuppressive niches that drive progression and therapeutic resistance is delineated.
Abstract
Background
Triple-negative breast cancer (TNBC) lacks stable druggable targets, is highly aggressive, and exhibits marked heterogeneity; consequently, therapeutic variability is often determined not only by tumor cell-intrinsic states but also by the immune-stromal ecology of the tumor microenvironment (TME) and its modes of spatial organization. The TNBC TME is jointly shaped by adaptive and innate immune cells, fibroblasts and the extracellular matrix, the vascular-hypoxia-lymphatic axis, and neural components, whose tissue-scale co-localization and boundary architecture underlie distinct phenotypes such as immune activation, immune exclusion, and immune desert.
MAIN BODY
Recent advances in single-cell sequencing, spatial transcriptomics, and multiplex imaging now enable in situ characterization of cellular composition, functional states, spatial positioning, and local interactions, thereby grounding complex multicellular crosstalk in observable microanatomical patterns. Focusing on recurrent constraints on T-cell entry, intratumoral positioning and productive contact, and the maintenance of effector function, this Review synthesizes the spatial heterogeneity of adaptive immunity and local immune organization, and delineates how myeloid programs and neutrophil extracellular trap (NET) formation, cancer-associated fibroblast (CAF) subsets and extracellular matrix (ECM) barriers, aberrant vasculature and hypoxia-linked metabolism, and the tumor-nerve signaling axis cooperatively shape immunosuppressive niches that drive progression and therapeutic resistance. We further summarize spatial neighborhoods/niches that are reproducibly identifiable across cohorts in TNBC (e.g. hypoxic niches, the stromal-myeloid axis formed by co-localized CA9+ CAFs and SPP1+ macrophages, and tertiary lymphoid structure (TLS)-associated immune-activated units) and discuss their associations with prognosis and therapeutic response.
Conclusions
Finally, integrating progress in TME-targeting clinical studies with window-of-opportunity sampling paradigms, we propose incorporating spatial neighborhood features and interaction signatures into stratification and dynamic assessment, and developing combination strategies centered on relieving myeloid suppression, remodeling stromal barriers, and correcting vascular/metabolic niches, with the goal of improving precision prediction and durable benefit of immunotherapy in TNBC.
Conclusions
Finally, integrating progress in TME-targeting clinical studies with window-of-opportunity sampling paradigms, we propose incorporating spatial neighborhood features and interaction signatures into stratification and dynamic assessment, and developing combination strategies centered on relieving myeloid suppression, remodeling stromal barriers, and correcting vascular/metabolic niches, with the goal of improving precision prediction and durable benefit of immunotherapy in TNBC.
Although immunocheckpoint blocking therapy has been successful in a variety of cancers, its long-term response is still rare. The difference between initial clinical benefits and persistent disease control reflects the complexity of intratumor immunomodulation. People’s attention is increasingly shifting from a single group of cells to the spatial environment in which these cells live. Tumor cells, immune cells and interstitial components cannot function independently; on the contrary, they form a local tissue structure, and their composition and structure affect immune activity. Technologies such as Co-Detection by Indexing (CODEX), Imaging Mass Cytometry (IMC), and multiple ion beam imaging (MIBI) can now directly detect these spatial relationships while measuring dozens of proteins at a single cell resolution. Therefore, the spatially defined immunosuppressive niche has become an important framework for explaining how local cell interactions lead to immune dysfunction and therapeutic resistance. These studies reveal that immune cells, stromal cells, and malignant cells form a highly ordered spatial network, synergistically regulated through direct contact, cytokine signaling, and metabolic interactions. This coordinated cellular network forms a local immunosuppressive microenvironment, thereby maintaining immune escape, tumor progression, and treatment resistance. Recent research has also uncovered previously unknown immunosuppressive cell states and their spatial interaction patterns, characteristics closely related to disease prognosis, recurrence risk, and immunotherapy response. Therefore, tumor immunology research is shifting from the characterization of single cell populations to the exploration of spatially organized functional ecosystems. This article reviews the latest advances in the field of space-based single-cell proteomics and summarizes current research findings on the cellular composition, spatial structure, and regulatory mechanisms of the immunosuppressive microenvironment. Furthermore, we explore the emerging clinical value of space biomarkers and interaction networks in patient stratification, therapeutic target identification, and precision immunotherapy.
Hao Chai, Lang Wu, Xiaopeng Chen et al.· Frontiers in Immunology· 0 citations
Breast cancer immunity depends on more than the number of immune cells in a tumor. It is also shaped by where those cells sit, which neighbors they contact, and what functional states they adopt locally. Tumor-associated macrophages (TAMs) and T cells are a key pairing in this setting. Depending on tissue context, their crosstalk may support cytotoxic immunity, reinforce immune exclusion, promote T-cell exhaustion, or weaken therapeutic response. Spatial technologies now allow these states to be examined in intact tumor sections rather than inferred from dissociated or bulk samples. Antibody-based imaging approaches, including imaging mass cytometry, MIBI, and CODEX, together with high-plex transcriptomic platforms such as MERFISH, Xenium, CosMx, Visium, GeoMx, and related methods, have revealed inflamed, excluded, myeloid-rich, stromal-barrier, and tertiary lymphoid structure-associated niches in breast cancer. However, spatial maps alone cannot establish mechanism. Cells that lie close together may not necessarily interact, and computational tools, including ligand-receptor scoring, graph-based neighborhood modeling, and spatial biomarker prediction, can only prioritize candidate macrophage-T cell programs. Functional validation remains essential. In this mini review, we discuss how spatial omics, computational modeling, organoid and explant cultures, microfluidic models, perturbation assays, and therapeutic testing can be linked to study macrophage-T cell crosstalk. We highlight a practical workflow in which spatial maps generate hypotheses, experimental systems test causality, and post-treatment profiling determines whether candidate interactions are remodeled by therapy.
Immunotherapy has transformed the therapeutic landscape of advanced cervical cancer, yet clinical benefit remains limited by a highly heterogeneous and immunosuppressive tumor microenvironment. Traditional paradigms, including binary M1/M2 macrophage polarization and models that interpret T-cell dysfunction solely through checkpoint expression, are insufficient to capture the localized intercellular dynamics that drive immune evasion. Recent advances in single-cell and spatial multi-omics have fundamentally reshaped our understanding of this landscape. In this review, we synthesize emerging high-dimensional atlases to reframe macrophage–T-cell crosstalk from simple ligand–receptor interactions into a spatially organized ecological model. We highlight the paradigm shift toward highly resolved myeloid programs, particularly SPP1+ and C1QC+ macrophage states, and discuss how these programs interact with stromal barriers, regulatory T cells, and metabolic checkpoints to restrict, exclude, or functionally constrain effector T cells within suppressive niches. Crucially, we position persistent high-risk human papillomavirus infection not merely as an initiating carcinogenic trigger, but as an upstream and continuous programmer that rewires innate immune sensing, including context-dependent cGAS–STING-related circuits, to stabilize local immune tolerance throughout disease progression. Finally, we propose translational strategies for distilling complex multi-omic atlases into pathology-compatible prognostic and predictive biomarker signatures. Ultimately, by deciphering these spatially organized networks, this review aims to provide actionable translational insights for targeting macrophage vulnerabilities, guiding biomarker-driven combinatorial immunotherapies, and overcoming immune resistance in cervical cancer.
Li Huang, Nan Lin, Hao Li et al.· Frontiers in Immunology· 0 citations
This study comprehensively maps the coevolution of malignant thyrocyte plasticity and the immunosuppressive metastatic niche in thyroid cancer and provides a robust molecular rationale for developing next-generation immunotherapeutic strategies tailored to thyroid cancer.
Shu-hang Xu, Yaorong Su, Senmin Zhang et al.· Oncoimmunology· 0 citations
Tumor immunity is increasingly understood not only through the cellular composition of the tumor microenvironment, but also through spatially organized local niches that can help determine where immune recognition is initiated, constrained, suppressed, or therapeutically restored. This review develops an organ-conditioned and evidence-graded framework for tumor immunological niches as spatially localized, interaction-dependent, functionally consequential, and dynamically remodeled units. Rather than reproducing a general taxonomy of cancer immune niches, we focus on how shared niche-forming mechanisms are implemented differently by organ-specific tissue rules. We first distinguish the niche concept from broad tumor microenvironment descriptions, immune infiltration, immune compartments, and tertiary lymphoid structures. We then propose an operational evidence hierarchy that separates spatial association, recurrent interaction, functional consequence, perturbation-based validation, and therapeutic actionability. Next, we synthesize core mechanisms of niche formation, including tumor-intrinsic signaling, stromal and extracellular-matrix scaffolding, chemokine and cytokine wiring, vascular-hypoxic-metabolic boundaries, myeloid-centered suppression, and tissue-resident immune imprinting. Brain and lung tumors are treated as two organizing paradigms: immune-restricted niche architecture in the central nervous system and inflammation-primed niche architecture in the lung. Oral, liver, and pancreatic tumors are discussed comparatively to show how mucosal-microbial, tolerogenic-metabolic, and desmoplastic immune-exclusion rules reshape shared niche mechanisms. We further separate tumor-specific evidence, inflammatory analogies, and hypothesis-generating parallels to avoid overextending chronic inflammation or fibrosis models. Finally, we examine how niche architecture produces T-cell exclusion, antigen-presentation failure, suppressive myeloid-stromal feedback, and therapeutic resistance, and how release, access, and licensing strategies may guide organ-tailored combinations when supported by adequate evidence. This review argues that tumor immunological niches may serve as meso-level analytical units linking spatial organization, organ context, evidence strength, inflammatory parallels, and therapeutic vulnerability when their evidentiary status is explicitly defined.
Zhuo Zhang, Yunyi Dong, Jin-Chao Li et al.· Frontiers in Immunology· 0 citations
ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is among the most aggressive human malignancies and has an extremely poor prognosis. Its progression is largely driven by a highly complex and immunosuppressive tumor microenvironment (TME), highlighting the urgent need for a deeper understanding of its molecular mechanisms. Recent advances in single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) have provided unprecedented opportunities to dissect cellular heterogeneity, spatial organization, and gene expression dynamics within the TME. In this review, we summarize the major scRNA-seq and ST technologies and their unique strengths in cancer research and highlight their integrated applications in revealing PDAC heterogeneity, stromal–immune interactions, and mechanisms of therapeutic resistance. We further discuss how these approaches can inform biomarker discovery and guide the development of novel therapeutic strategies. Together, these findings suggest that integrated single-cell and spatial transcriptomics offers transformative potential to advance precision oncology and improve outcomes for patients with pancreatic cancer.
Mengting Luo, Feng Shen, Wanli Xu et al.· Cancer Biology & Therapy· 0 citations