---
title: "Tumor Microenvironment in Triple-Negative Breast Cancer: Immune Evasion to Precision Immunotherapy"
id: "frontiers-in-immunology-10-decoding-the-tumor-microenvironment-of-triple-negative-breast-cancer-from"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-10-decoding-the-tumor-microenvironment-of-triple-negative-breast-cancer-from"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1887760"
published_at: "2026-08-25T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Tumor Microenvironment in Triple-Negative Breast Cancer: Immune Evasion to Precision Immunotherapy
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/frontiers-in-immunology-10-decoding-the-tumor-microenvironment-of-triple-negative-breast-cancer-from
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1887760)
- **Published At:** 2026-08-25T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The source provided is a Frontiers in Immunology web page shell and navigation; the full article text for "Decoding the tumor microenvironment of triple-negative breast cancer: from immune evasion to precision immunotherapy" was not present in the supplied source. - Available items on the page include site navigation, journal identification (Frontiers in Immunology), links to journal sections, and author resources such as submission and author guidelines. - The page lists numerous journal sections relevant to cancer research, including **Cancer Immunity and Immunotherapy**, T cell biology, dendritic cells and macrophages, cytokines, and methods/technologies in immunology. - Repeated site navigation elements and links were present: About us, publishing model, services, and more-from-Frontiers links. - Specific article-level content (abstract, introduction, methods, results, discussion, figures, and conclusions) and any study data, authorship, dates, or recommendations were not reported in the source. - Submission-related links visible included “Submit manuscript,” “Submit data,” author guidelines, fee policy, and contact editorial office — indicating author-facing resources but no article details. - Because the underlying article text is missing, no clinical facts, trial outcomes, mechanistic details, or therapeutic recommendations about triple-negative breast cancer (TNBC) or its tumor microenvironment can be extracted or summarized from the source.
## Clinical Analysis & Structured Key Points
Frontiers | Decoding the tumor microenvironment of triple-negative breast cancer: from immune evasion to precision immunotherapy MINI REVIEW article Front. Immunol. , 25 August 2026 Sec. Cancer Immunity and Immunotherapy Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1887760 Published in Frontiers in Immunology Cancer Immunity and Immunotherapy 7 impact factor 11.3 citescore Part of a Research Topic Decoding the tumor immune microenvironment through multi-omics and signaling pathway analysis in cancer Submission open 34k views 23 articles Editor & Reviewers Edited by H J Hearn Jay Cho Reviewed by X Z XIAO ZHENG Outline Figures and Tables Figure 1 View in article MINI REVIEW article Front. Immunol. , 25 August 2026 Sec. Cancer Immunity and Immunotherapy Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1887760 Decoding the tumor microenvironment of triple-negative breast cancer: from immune evasion to precision immunotherapy H C Hongyu Cao † M T Meicheng Tao † X Q Xuepeng Qin * H G Hong Guo * Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China Article metrics View details Abstract Triple-negative breast cancer (TNBC) represents a highly aggressive breast cancer subtype characterized by the absence of estrogen receptor, progesterone receptor, and HER2 expression, resulting in limited targeted therapeutic options and poor clinical outcomes. Although immune checkpoint inhibitors (ICIs) have transformed the treatment landscape of TNBC, therapeutic responses remain restricted to a subset of patients due to substantial heterogeneity within the tumor immune microenvironment (TIME). Increasing evidence indicates that immune evasion in TNBC is driven by complex interactions among tumor cells, immune populations, stromal components, and metabolic alterations. This review summarizes the dynamic landscape of the TNBC immune microenvironment, focusing on the functional roles of tumor-infiltrating lymphocytes, tumor-associated macrophages, tumor-associated neutrophils, natural killer cells, and myeloid-derived suppressor cells in regulating antitumor immunity and therapeutic resistance. We further discuss clinical advances of ICIs, including monotherapy and chemoimmunotherapy approaches, as well as emerging therapeutic strategies involving small molecules, bispecific antibodies, antibody–drug conjugates, and novel immune-based modalities. 1 Introduction Triple-negative breast cancer (TNBC) accounts for approximately 15–20% of breast cancer cases and represents one of the most clinically aggressive molecular subtypes due to its high proliferative capacity, early metastatic potential, and limited availability of effective targeted therapies ( 1 – 3 ). Unlike hormone receptor-positive or HER2-positive breast cancers, TNBC lacks expression of estrogen receptor, progesterone receptor, and HER2, resulting in chemotherapy historically serving as the primary systemic treatment option ( 4 ). However, intrinsic and acquired chemotherapy resistance, together with frequent disease recurrence and metastasis, continues to contribute to unfavorable clinical outcomes ( 5 , 6 ). Notably, TNBC exhibits greater immune infiltration and higher tumor mutational burden compared with other breast cancer subtypes, suggesting a unique biological context for immunotherapeutic intervention ( 7 ). The tumor immune microenvironment (TIME) plays a fundamental role in determining TNBC progression, immune escape, and therapeutic response ( 8 ). Interactions between malignant cells and immune components, including cytotoxic T cells, regulatory T cells, macrophages, neutrophils, natural killer cells, and myeloid-derived suppressor cells, collectively shape an immunosuppressive niche that limits effective antitumor immunity ( 9 ). Although immune ICIs have achieved clinical success in selected TNBC populations, primary and acquired resistance remain major challenges ( 10 ). Therefore, a comprehensive understanding of immune regulation within the TNBC microenvironment is essential for developing rational combination strategies and advancing precision immunotherapy. 2 Tumor microenvironment in triple-negative breast cancer 2.1 Lymphocytic elements within the immune microenvironment 2.1.1 CD8 + T cell subsets in triple-negative breast cancer In TNBC, CD8 + T cells constitute the principal cytotoxic lymphocyte subset orchestrating antitumor surveillance ( 11 ). Following the recognition of tumor-associated antigens presented via MHC-I molecules, naive CD8 + T cells differentiate into effector cytotoxic T lymphocytes (CTLs). These CTLs eradicate malignant cells primarily through the exocytosis of perforin and granzymes, the secretion of IFN-γ, and the induction of target cell apoptosis ( 12 , 13 ). Consistent with their antitumor function, increased CD8 + T-cell infiltration is associated with improved prognosis, prolonged survival, and enhanced therapeutic responses in TNBC ( 11 , 14 ). However, the antitumor activity of CD8 + T cells is determined not only by their abundance but also by their functional state ( 15 ). Persistent antigen stimulation and immunosuppressive signals within the TNBC TME can induce CD8 + T-cell exhaustion, characterized by sustained expression of inhibitory receptors, including PD-1, TIM-3, and LAG-3, accompanied by reduced cytokine production and impaired cytotoxic capacity ( 16 – 18 ). CD8 + T-cell exhaustion represents a heterogeneous continuum rather than a terminal state ( 19 ). Progenitor exhausted/stem-like CD8 + T cells expressing TCF1 retain self-renewal capacity and proliferative potential, and these populations are considered critical responders to immune checkpoint blockade ( 20 , 21 ). Conversely, terminally exhausted CD8 + T cells exhibit profound epigenetic scarring and display minimal functional rejuvenation following ICB therapy ( 22 , 23 ). Furthermore, memory-like CD8 + T cell subsets contribute to durable immunological surveillance by conferring enhanced persistence and robust recall responses against recurrent tumor antigens ( 24 – 26 ). 2.1.2 CD4 + helper t cells in triple-negative breast cancer CD4 + helper T cells represent a heterogeneous population of adaptive immune cells that coordinate antitumor immune responses through functional specialization into distinct subsets, including Th1, Th2, Th17, and follicular helper T cells (Tfh) ( 27 , 28 ). CD4 + T cells primarily regulate immune responses by modulating the activation and function of cytotoxic lymphocytes, antigen-presenting cells, B cells, and innate immune populations ( 29 ). In cancer immunity, CD4 + T-cell subsets critically influence the tumor microenvironment toward immune activation or immune tolerance ( 30 – 32 ). Among these subsets, Th1 cells are generally considered important mediators of antitumor immunity due to their production of IFN-γ, which enhances antigen presentation, promotes macrophage activation, and supports CD8 + T-cell-mediated tumor killing ( 33 – 35 ). Conversely, Th2 and Th17 responses may exhibit context-dependent effects in tumor progression ( 36 ). While Th17-derived cytokines can enhance immune recruitment under certain conditions, chronic IL-17 signaling may promote tumor-associated inflammation, angiogenesis, and immune suppression ( 37 ). Tfh cells, characterized by expression of CXCR5 and PD-1, regulate B-cell maturation and antibody production within tertiary lymphoid structures, which have been associated with improved immunotherapy responsiveness in several malignancies ( 38 – 40 ). In TNBC, CD4 + helper T cells contribute substantially to shaping the immune landscape and therapeutic response ( 41 ). Compared with hormone receptor-positive breast cancer subtypes, TNBC generally exhibits higher immune infiltration and greater enrichment of immune-related transcriptional signatures, suggesting increased immune interaction within the tumor microenvironment ( 42 ). However, the functional state of CD4 + T cells is highly dependent on local cytokine networks and tumor-derived suppressive signals. Persistent exposure to immunosuppressive factors, including TGF-β, IL-10, and metabolic stress signals, can induce CD4 + T-cell dysfunction and impair effective immune surveillance ( 43 ). Therefore, understanding the balance between immune-stimulatory and immune-regulatory CD4 + T-cell subsets is essential for developing rational immunotherapeutic strategies in TNBC. 2.1.3 Regulatory T cells in triple-negative breast cancer Tregs represent a specialized immunosuppressive CD4 + T-cell population that maintains peripheral immune tolerance under physiological conditions ( 44 ). However, within the tumor microenvironment, Tregs are frequently recruited and expanded by tumor-derived chemokines and inflammatory signals, where they become critical mediators of immune escape by actively suppressing antitumor immune responses ( 45 , 46 ). In TNBC, Tregs are particularly enriched compared with other breast cancer subtypes, and increased infiltration of FOXP3 + Tregs has been detected in a substantial proportion of tumors ( 47 ). The accumulation of Tregs within TNBC lesions is associated with reduced immune activation, impaired effector T-cell function, and resistance to immune-based therapies ( 48 , 49 ). Mechanistically, Tregs suppress antitumor immunity through multiple complementary pathways. Tregs secrete immunosuppressive cytokines, including IL-10 and TGF-β, which inhibit cytotoxic T lymphocyte activity, reduce inflammatory cytokine production, and promote the development of an immunosuppressive tumor microenvironment ( 44 , 50 ). Tregs express high levels of immune checkpoint molecules, particularly CTLA-4, which competitively binds CD80/CD86 on antigen-presenting cells and reduces their costimulatory capacity, thereby limiting effective priming of tumor-reactive T cells ( 51 ). Furthermore, Treg-derived CTLA-4 signaling can induce indoleamine 2,3-dioxygenase (IDO) expression in dendritic cells, resulting in tryptophan depletion and accumulation of immunosuppressive metabolites that further inhibit effector T-cell proliferation and function ( 52 ). Tregs exert metabolic suppression through competition for essential growth factors, particularly IL-2. By constitutively expressing high levels of CD25, Tregs efficiently consume extracellular IL-2, depriving conventional CD4 + and CD8 + effector T cells of this critical survival and proliferation signal, thereby weakening antitumor immune responses ( 53 ). Tregs can directly suppress natural killer cells, dendritic cells, and macrophage activation through cell–cell interactions and inhibitory receptor signaling, further reinforcing immune tolerance within TNBC lesions ( 54 , 55 ). 2.2 Tumor-associated macrophages in triple-negative breast cancer TAMs are critical regulators of tumor progression, immune escape, and therapeutic resistance in TNBC ( 56 ). Depending on environmental signals, macrophages can adopt distinct functional states, including pro-inflammatory M1-like and immunosuppressive M2-like phenotypes ( 57 , 58 ). In the TNBC TME, tumor-derived factors such as IL-10, TGF-β, and macrophage colony-stimulating factor (M-CSF) promote macrophage recruitment and polarization toward M2-like TAMs, thereby facilitating tumor growth and immune suppression ( 57 , 59 ). TNBC exhibits increased infiltration of TAMs, particularly CD163 + and CD204 + macrophage populations. Elevated accumulation of these M2-associated TAMs is correlated with aggressive clinicopathological characteristics, including enhanced tumor proliferation, vascular invasion, poor differentiation, and unfavorable prognosis ( 58 ). TAMs contribute to TNBC progression by secreting immunosuppressive cytokines, including IL-10 and TGF-β, which impair CD8 + T-cell-mediated cytotoxicity, while also promoting angiogenesis, extracellular matrix remodeling, and metastatic dissemination ( 60 , 61 ). TAMs have emerged as promising therapeutic targets. Inhibition of the CSF1R, a key regulator of macrophage survival and differentiation, can reduce TAM accumulation and enhance antitumor immunity ( 62 , 63 ). However, TAM-targeting strategies alone often show limited efficacy, highlighting the need for combination approaches. For example, combined targeting of CSF1R and CXCR2 signaling has been shown to decrease TAMs while improving responses to PD-1 blockade ( 64 ). These findings emphasize the importance of targeting the broader immunosuppressive myeloid network and provide a rationale for integrating TAM-directed therapies with immune checkpoint inhibitors in TNBC. 2.3 Tumor-associated neutrophils in triple-negative breast cancer Tumor-associated neutrophils (TANs) exhibit functional plasticity and can be broadly classified into antitumor N1 and tumor-promoting N2 phenotypes. The polarization process is strongly influenced by cytokine signaling within the TME ( 65 ). Pro-inflammatory signals, including IFN-β and other IFN-associated pathways, promote N1-like neutrophil activation characterized by enhanced inflammatory responses and tumoricidal activity ( 66 ). In contrast, tumor-derived TGF-β signaling drives TAN polarization toward an N2-like phenotype, which exhibits immunosuppressive functions and promotes tumor growth through secretion of VEGF-A, CXCL1, CXCL2, and matrix-remodeling factors ( 67 – 69 ). In TNBC, increased TAN infiltration and elevated neutrophil-to-lymphocyte ratios (NLRs) are frequently associated with poor prognosis and reduced therapeutic responses ( 70 – 72 ). TANs promote immune escape by suppressing cytotoxic lymphocyte activity, enhancing angiogenesis, and facilitating metastatic progression. Recruitment of neutrophils into tumor tissues is primarily regulated by C-X-C chemokine receptors, particularly CXCR1 and CXCR2, making these pathways attractive therapeutic targets ( 73 , 74 ). The CXCR1/2 inhibitor reparixin has been evaluated in clinical studies involving metastatic breast cancer patients receiving chemotherapy ( 75 , 76 ). Early-phase trials demonstrated acceptable safety profiles and clinical feasibility, although limited antitumor efficacy indicated that CXCR1/2 inhibition may require combination with other immunomodulatory strategies ( 77 ). Therefore, targeting TAN recruitment and polarization, together with immune checkpoint blockade or other TME-modulating approaches, may represent a promising strategy for overcoming immune resistance in TNBC. 2.4 NK cells and MDSCs in triple-negative breast cancer Natural killer (NK) cells and myeloid-derived suppressor cells (MDSCs) represent two functionally distinct but highly interconnected immune populations that critically regulate antitumor immunity ( 78 , 79 ). NK cells are essential components of innate immune surveillance and eliminate malignant cells through multiple mechanisms, including perforin/granzyme-mediated cytotoxicity, death receptor signaling, and antibody-dependent cellular cytotoxicity mediated by CD16/FcγRIII ( 80 , 81 ). In TNBC, increased infiltration and activation of NK cells are generally associated with improved immune surveillance and favorable clinical outcomes ( 82 , 83 ). However, the immunosuppressive TME, characterized by elevated levels of TGF-β, IL-10, hypoxia, and metabolic stress, can impair NK-cell cytotoxic function and promote an exhausted phenotype ( 84 , 85 ). Therefore, restoring NK-cell activity through cytokine stimulation, metabolic modulation, or combination with immune checkpoint blockade represents a promising therapeutic strategy ( 86 , 87 ). Conversely, MDSCs are major immunosuppressive myeloid populations that accumulate in TNBC and contribute to tumor progression and immune escape ( 88 , 89 ). Based on phenotypic characteristics, MDSCs are broadly classified into monocytic (M-MDSCs) and polymorphonuclear/granulocytic (PMN-MDSCs) subsets ( 88 , 90 ). These cells suppress antitumor immunity by inhibiting CD8 + T-cell and NK-cell function through mechanisms involving ARG1, inducible iNOS, ROS, and immunosuppressive cytokine production ( 91 ). Furthermore, MDSCs promote angiogenesis, metastasis, and resistance to immune checkpoint inhibitors by maintaining an immunosuppressive myeloid network within the TME ( 92 , 93 ). Targeting MDSCs and restoring NK-cell activity have therefore emerged as potential approaches to enhance immunotherapy efficacy in TNBC. For example, inhibition of CSF1R and CXCR2 signaling has been shown to reduce suppressive myeloid populations, including TAMs and MDSCs, while improving responses to PD-1 blockade ( 94 ). In sum, the dynamic balance between cytotoxic NK-cell activity and MDSC-mediated immune suppression represents an important determinant of TNBC immune responsiveness and provides opportunities for developing rational combination immunotherapies ( 95 , 96 ) ( Supplementary Figure 1 ). 3 Clinical advances of immune checkpoint inhibitors in TNBC 3.1 PD-1/PD-L1 inhibitor As a PD-1 inhibitor, pembrolizumab has demonstrated preliminary antitumor activity as a single-agent therapy in previously treated metastatic TNBC ( 97 ). However, its overall efficacy remains limited. Early clinical trials, including KEYNOTE-012 and KEYNOTE-086, reported objective response rates (ORRs) ranging approximately from 5% to 21%, indicating that although immune checkpoint blockade can provide durable clinical benefits for a subset of patients, the majority of individuals derive limited therapeutic benefit from monotherapy ( 98 – 100 ). Patients with PD-L1-positive tumors, particularly those with a combined positive score (CPS) ≥10, exhibited higher response rates and improved survival outcomes following pembrolizumab treatment, highlighting PD-L1 expression as an important predictive biomarker for immunotherapy responsiveness ( 101 ). Nevertheless, the clinical limitations of ICI monotherapy remain substantial, largely due to the highly heterogeneous immune landscape of TNBC ( 102 , 103 ). Primary resistance may arise from multiple factors, including intrinsic tumor genomic alterations, insufficient infiltration of tumor-infiltrating lymphocytes (TILs), impaired antigen presentation, and activation of alternative immunosuppressive pathways ( 104 – 106 ). Notably, the anti-PD-L1/CTLA-4 bispecific antibody KN046 plus nab-paclitaxel for metastatic triple-negative breast cancer treatment (NCT03872791) ( 107 ). Therefore, although single-agent immunotherapy has introduced a novel therapeutic option for a proportion of TNBC patients, its restricted response rate and widespread resistance have driven extensive investigation into combination strategies aimed at enhancing antitumor immunity and overcoming the limitations of monotherapy. 3.2 Immunotherapy combined with chemotherapy The combination of immune checkpoint inhibitors with chemotherapy has become a standard first-line therapeutic strategy for advanced TNBC, supported by evidence from several pivotal phase III clinical trials ( 108 ). The IMpassion130 trial was the first landmark study demonstrating that atezolizumab combined with nab-paclitaxel significantly prolonged overall survival in patients with PD-L1-positive metastatic TNBC, establishing a new paradigm for immune-based combination therapy in this disease setting ( 109 ). Subsequently, the KEYNOTE-355 trial further consolidated the role of chemoimmunotherapy by demonstrating that pembrolizumab plus chemotherapy (nab-paclitaxel, paclitaxel, carboplatin-based regimens) significantly improved survival in patients with metastatic TNBC harboring a CPS ≥10 ( 110 ). The mechanisms underlying the immunomodulatory effects of chemotherapy are multifaceted. A key mechanism involves the induction of immunogenic cell death, through which chemotherapeutic agents not only eliminate tumor cells but also promote the release of danger-associated molecular patterns (DAMPs), tumor antigens, and inflammatory mediators that stimulate adaptive immune respo
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