tumor microenvironment

Overview

The tumor microenvironment (TME) refers to the complex, dynamic ecosystem surrounding and infiltrating a malignant tumor, comprising not only cancer cells but also a heterogeneous mixture of stromal cells, immune cells, extracellular matrix components, blood vessels, and soluble signaling molecules. Far from being a passive bystander, the TME actively participates in regulating tumor initiation, progression, immune evasion, metastasis, and therapeutic resistance. Key cellular constituents include tumor-associated macrophages (TAMs), cytotoxic T cells, regulatory T cells, dendritic cells, natural killer (NK) cells, B cells, cancer-associated fibroblasts, myeloid-derived suppressor cells (MDSCs), and neutrophils, all of which engage in intricate bidirectional crosstalk with neoplastic cells through cytokines, chemokines, Metabolites, and exosomes. The physical and chemical characteristics of the TME — including hypoxia, acidosis, elevated reactive oxygen species (ROS), and immunosuppressive metabolite gradients — collectively shape a milieu that frequently supports tumor survival and shields cancer cells from immune surveillance.

A defining hallmark of many TMEs is their immunosuppressive character, which drives resistance to both conventional therapies and modern immunotherapy. This immunosuppression is orchestrated through multiple overlapping mechanisms: the polarization of macrophages toward an M2-like, pro-tumorigenic phenotype; the accumulation of regulatory T cells and MDSCs; the co-expression of immune checkpoint molecules such as PD-1, PD-L1, LAG-3, TIGIT, VISTA, and B7-H3 (CD276); and the secretion of immunosuppressive cytokines such as transforming growth factor-beta (TGF-β) and IL-10. Understanding and therapeutically reprogramming the TME has emerged as one of the central challenges and opportunities in contemporary oncology, driving research across virtually every cancer type and treatment modality.

Focus of Latest Publications

Recent literature underscores the TME's centrality across a remarkably broad spectrum of cancer biology and therapeutic development, spanning immune cell regulation, metabolic reprogramming, stromal remodeling, drug delivery innovation, and multi-modal treatment strategies.

Immune Cell Dynamics and Checkpoint Regulation

A major focus of recent TME research concerns the behavior and therapeutic manipulation of immune cells within the tumor niche. Studies have demonstrated that PD-1 and LAG-3 are frequently co-expressed by T cells in the TME, where they synergistically drive T-cell exhaustion and immune escape, establishing a compelling rationale for dual checkpoint blockade strategies. Similarly, TIGIT has been identified in the TME of multiple lymphoma subtypes, including classical Hodgkin lymphoma, where its expression correlates with an immunosuppressive state. VISTA, another immune checkpoint regulator, has been shown to be induced by platelets within the ovarian tumor TME, revealing a previously underappreciated role for platelet-tumor interactions in facilitating immune evasion.

Regulatory B cells (Bregs) have emerged as significant contributors to TME immunosuppression in melanoma, mediating immune tolerance by inducing regulatory T cells and secreting TGF-β and IL-10. Conversely, the antigen-presenting cell (APC) function of B cells can be enhanced through metabolic reprogramming of fatty acid metabolism in the TME, offering a strategy to boost anticancer immunity in metastatic ovarian cancer. Innate immune cells, including macrophages, dendritic cells, and NK cells, constitute the majority of the TME and have been shown through clonal lineage tracing in human cancers to mediate anti-tumor immunity and shape immunotherapy responses. TAMs, in particular, exhibit remarkable plasticity: their polarization toward M1-like phenotypes — achieved through polymannose-guided repolarization, oncolytic vaccinia viruses encoding CD47 nanobodies, or macrophage metabolic reprogramming — has consistently been associated with improved antitumor outcomes. The proliferating macrophage (Prolif M) subset has been specifically implicated in driving immunosuppression and hepatocellular carcinoma (HCC) progression via the Rnaseh2c–Cdk9 axis and CCL2/CCR2-mediated CD8+ T cell exhaustion.

Neutrophil extracellular traps (NETs), DNA-protein complexes released by neutrophils within the TME, have garnered increasing attention for their roles in promoting cancer progression, metastasis, and immune modulation. A novel risk model incorporating MMP9, TLR8, and LILRB2 has linked NET formation to immune evasion in glioma. Strategies employing DNASE1-functionalized nanoparticles to spatiotemporally control NET release have demonstrated enhanced infiltration of NK cells and CD8+ T cells alongside a shift in macrophage and neutrophil polarization toward anti-tumor phenotypes, collectively reversing TME immunosuppression.

The chemokine-chemokine receptor axis has been highlighted as an emerging immunotherapeutic paradigm for TME reprogramming in solid tumors, with CXCL10 — regulated by the ZNF737 axis in bladder cancer and inducible by asiatic acid via HDAC8 inhibition in hepatocellular carcinoma — playing a key role in CD8+ T cell recruitment. Conversely, SPP1+ malignant cells and CXCR4+ TAM crosstalk have been shown to predict immunotherapy resistance in lung adenocarcinoma by fostering an immunosuppressive TME.

Myeloid-derived suppressor cells (MDSCs) expressing CD55 have been found to drive cancer immunoevasion by shaping the suppressive TME. Furthermore, the gut microbiota has been identified as an important external modulator of the tumor immune microenvironment, either fostering antitumor immunity through augmented antigen presentation and effector cell function, or constraining immune responses via regulatory networks and immunosuppressive myeloid polarization.

Hypoxia, Metabolic Reprogramming, and the Physical TME

Hypoxia within the TME represents a major barrier to effective immunotherapy. Recent work has demonstrated that hypoxia induces dysfunction in NK cells through mitochondrial dynamics mediated by DRP1, and that DRP1 depletion protects NK cells from this hypoxia-induced impairment, suggesting a metabolic vulnerability amenable to therapeutic intervention. More broadly, metabolic reprogramming — encompassing glycolysis, lipid metabolism, and amino acid metabolism — has been recognized as a core hallmark driving non-small cell lung carcinoma (NSCLC) progression and TME remodeling, transcending the classical Warburg effect to involve intricate cross-talk between cancer cells and stromal components. Lipid metabolism reprogramming has been shown to extensively reshape the TME, establishing metabolic crosstalk that drives immune evasion by starving cytotoxic T cells and natural killer cells of essential nutrients.

The physical properties of the TME also significantly affect treatment efficacy. In pancreatic cancer, losartan preconditioning has been shown to transiently convert a high-stiffness TME into a more compliant state, improving nanoparticle penetration and chemo-immunotherapy delivery. The acidic, hypoxic TME has been exploited for pH-responsive drug delivery systems, with nanocarriers designed to remain stable at physiological pH (7.4) but undergo rapid disassembly in the mildly acidic TME (pH 6.8), thereby concentrating therapeutic payloads at tumor sites. Glutathione (GSH) overexpression in the TME has similarly been leveraged to trigger biodegradation of nanozyme systems, enabling tumor-specific drug release coupled to oxidative stress amplification.

The USP1-mediated lipophagy-lipogenesis axis has been implicated in cholangiocarcinoma progression and immune evasion, illustrating how metabolic dysregulation and immunosuppression are deeply intertwined in some TME contexts. Ubiquitination dysregulation has further been proposed as a key driver of neuroendocrine prostate cancer (NEPC) lineage plasticity and TME remodeling, with integrated bulk and single-cell transcriptomic analyses defining ubiquitination-centered TME circuits of diagnostic and therapeutic relevance.

Cancer-Associated Fibroblasts and Stromal Remodeling

Cancer-associated fibroblasts (CAFs) have been identified as important TME modulators, and a recent local gene-editing approach targeting fibroblasts in tumors has uncovered a new CAF state with functional consequences for the broader TME composition and immune infiltration landscape. In pancreatic ductal adenocarcinoma (PDAC), the dense fibrotic stroma — partly maintained by CAFs — contributes to DNA repair-mediated resistance, drug efflux mechanisms, and an immunosuppressive TME, all of which must be overcome for effective treatment.

Exosomes and Intercellular Crosstalk

Tumor-derived exosomes have been established as powerful mediators of TME remodeling, influencing immune evasion, metastasis, and therapy resistance through mechanisms involving B7-H3 (CD276). In lung cancer, exosome-mediated crosstalk between immune cells and the TME drives immune evasion and therapeutic resistance. dendritic cell-derived exosomes are being explored as immunostimulatory vehicles capable of reprogramming the TME, while biomimetic proteolipid vesicles delivering small activating RNA can activate macrophage immunotherapy by repolarizing M2-polarized TAMs within the TME. Nerves have also been shown to stimulate cross-talk between gastric cancer cells and group 3 innate lymphoid cells, enhancing immunosuppression in the TME through neuro-immune interactions.

Therapeutic Strategies Targeting the TME

The immunosuppressive TME has become a primary therapeutic target across modalities. Oncolytic viruses and cytokine-based gene therapies are being developed to reprogram solid tumor TMEs, converting profoundly immunosuppressive niches into environments permissive to immune attack. Immune modulatory vaccines selectively targeting immunosuppressive TME elements represent another emerging approach. Bispecific T-cell engagers (BiTEs) and bispecific macrophage nano-engagers coupling dual checkpoint blockade with STING activation are being designed to overcome immune exclusion in "cold" TMEs. PD1-IL2 bispecific drugs integrating PD-1 blockade with engineered IL-2 variants precisely regulate TME immunity. 4-1BB agonists are being molecularly engineered to restrict their activation to the TME, reducing systemic toxicity. Targeted TNF has been shown to turn "cold" TMEs "hot," potentiating the activity of bispecific T-cell engagers.

CAR-T cell therapy, while transformative in hematological malignancies, faces profound challenges in solid tumors from TME-mediated suppression. Strategies to overcome this include engineering CAR-T cells with inducible GLUT3 expression to enhance metabolic fitness in the glucose-poor TME of glioblastoma, and harnessing endogenous CD28 co-stimulation to drive persistent CAR-T cell activity. Intratumoral injection of virus-like particles containing TLR9 agonists combined with systemic anti-PD-1 therapy has been shown to modify the TME to induce a stronger antitumor T-cell response. Adoptive cell transfer therapy more broadly continues to be limited by TME-mediated suppression, and thermal sonogenetics is being explored to enhance ACT efficacy in this context.

For solid tumors with "hot" TMEs, the tumor immune microenvironment (TIME) — a subset concept referring specifically to the immune cell compartment — has been shown to critically modulate responses to immune checkpoint inhibitors (ICIs) in hepatocellular carcinoma, with multimodal sequencing identifying synergistic resistance mechanisms. The gut microbiota-metabolite axis and genetic signatures of the TME have been increasingly associated with ICI outcomes, underscoring the systemic dimensions of TME biology. In mismatch repair-deficient (dMMR) colon cancer, a CD8-rich TME confers sensitivity to ICI therapy, while mismatch repair-proficient (pMMR) tumors with a "cold" TME exhibit resistance despite identical systemic immune exposure.

Novel nanoparticle platforms — including MOF-based drug delivery systems, self-immolative nanotheranostics, and pH-responsive polymeric-peptide complexes — are being designed to exploit or remodel the TME, enabling synergistic combinations of chemotherapy, photodynamic therapy (PDT), sonodynamic therapy (SDT), and immunotherapy. The cGAS-STING pathway has been identified as a key target for converting "cold" TMEs to "hot" ones through platinum(IV) prodrug nanoparticles, establishing durable immune memory in murine nasopharyngeal carcinoma models. Photodynamic priming combined with minocycline has been shown to overcome chemoresistance in pancreatic cancer by reprogramming the pancreatic tumor immune microenvironment in vivo.

Key Publications

• Jun Reversing immunotherapy resistance in cold tumors by weaponizing pyroptosis with a dual-payload nanotuner. (Journal of controlled release : official journal of the Controlled Release Society, 2026, PMID 42314991): "This dual-pathway engagement enhances the release of pro-inflammatory cytokines and remodels the tumor immune microenvironment."
• Jun Knowledge mapping and research trends of chimeric antigen receptor T-cell immunotherapy in breast cancer: A bibliometric and visual analytics study. (Human vaccines & immunotherapeutics, 2026, PMID 42316771): "Keyword clustering and timeline visualization indicated that the terms "in vivo," "tumor microenvironment (TME)," and "targeted therapy" have remained highly active in recent years."
• Jun Glycosylated extracellular matrix drives immune suppression by modulating macrophage-T cell crosstalk in triple-negative breast cancer. (Nature communications, 2026, PMID 42303597): "Using decellularized human TNBC samples, we show that targeted enzymatic removal of these ECM glycans modifies the tumor immune microenvironment."
• Jun Biomarker study of pembrolizumab in patients with advanced rare cancers. (Cell reports. Medicine, 2026, PMID 42167248): "These findings suggest that tumor immune microenvironment features may serve as predictive markers beyond genomic assays and highlight immune cell recruitment during therapy in moderately infiltrated tumors."
• Jun Tumor immune microenvironment reconstitution in patient-derived organoids enables therapy modeling for NSCLC. (Cell reports methods, 2026, PMID 42134319): "Despite various therapeutic options, treatment resistance is common, underscoring the need for effective combination therapies and reliable pre-clinical models for patient-specific evaluation."
• Jun Targeting DNA repair with a Pt(IV) prodrug nanoparticle potentiates chemo-immunotherapy for nasopharyngeal carcinoma through cGAS-STING activation. (Journal of controlled release : official journal of the Controlled Release Society, 2026, PMID 41966338): "In murine NPC models, NP2 effectively suppresses tumor progression and reshapes the TME, converting "cold" tumors into "hot" tumors and establishing durable immune memory."
• Jun USP1-mediated lipophagy-lipogenesis axis drives cholangiocarcinoma progression and immune evasion. (Journal for immunotherapy of cancer, 2026, PMID 42259603): "Cholangiocarcinoma (CCA), a malignancy arising from biliary epithelial cells, features a tumor microenvironment (TME) characterized by metabolic dysregulation and immunosuppression."
• Jun Ubiquitination-anchored signature defines neuroendocrine prostate cancer: hub genes and single-cell ecosystem insights from integrated bioinformatics analysis of public transcriptomic datasets. (The aging male : the official journal of the International Society for the Study of the Aging Male, 2026, PMID 42249833): "We hypothesized that dysregulated ubiquitination underpins NEPC lineage plasticity and that integrating bulk and single-cell transcriptomes would define a ubiquitination-centered signature and tumor microenvironment (TME) circuits of diagnostic and therapeutic relevance."
• Jun Clonal lineage tracing of innate immune cells in human cancer. (Cancer cell, 2026, PMID 42242233): "Innate immune cells constitute the majority of the tumor microenvironment (TME) and mediate anti-tumor immunity and immunotherapy responses."
• Jun 3D chromatin architecture-related genes orchestrate LUAD evolution and therapy resistance: insights from integrative machine learning and spatial single-cell mapping. (Functional & integrative genomics, 2026, PMID 42240917): "regulation of the tumor microenvironment (TME)"