Aug 2026· Frontiers in Immunology· Vol 17· 0 citations· 157 references
Medicine
TL;DR
A 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.
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.
INTRODUCTION
Triple-negative breast cancers (TNBCs) are a type of breast cancer (BC) characterized by the absence of ER, PR, and HER2 expression. They account for 10-15% of invasive BC cases and are known for being aggressive and highly metastatic. TNBC patients face limited effective treatment options due to the inherent heterogeneity of the disease and a lack of targetable receptor molecules.
METHODS
Chemotherapy, used as part of neoadjuvant or adjuvant therapy, remains the major treatment recourse but is associated with toxicity, resistance, and relapse. Unlike other BCs, TNBCs' tumor microenvironment (TME) features many tumor-associated antigens (TAAs) and significant lymphocyte infiltration, such as Tc cells and other immune cells, e.g., NK cells. The collection of relevant studies herein was done by typing the keywords "Targeted Immunotherapy for Triple Negative Breast Cancer" on Google and PubMed databases, which were henceforth retrieved with a focus on recent attempts.
RESULTS
TNBCs are considered immunologically "hot". However, the presence of significant immunosuppressive cells, including Tregs, TAMs, and MDSCs, along with inhibitory cytokines, such as IL- 10 secreted by these cells, expression of immunosuppressive molecules, such as PD-1, PD-L1, and CTLA-4, weakens the anti-tumor response through immunosuppressive actions.
DISCUSSION
TNBC-TME is a target for immunotherapy. Current immunotherapeutic strategies target the TNBC TME using immune checkpoint inhibitors (ICIs) against PD-1, PD-L1, and CTLA-4. Additionally, several studies focus on developing vaccines targeting immunosuppressive cells and molecules of the TNBC TME.
CONCLUSION
This review highlights advancements in immunotherapy strategies for mitigating TNBC, with a particular focus on targeting immunosuppressive molecules.
Parth Malik, V. Patel, R. Maitra et al.· Current Drug Targets· 0 citations
Triple-negative breast cancer (TNBC) is characterized by high metastatic potential, frequent recurrence and limited targeted regimens. The chemokine network acts as a central orchestrator, reshaping its tumor immune microenvironment (TIME) and determining therapeutic responsiveness. Yet its clinical translation remains hindered by network complexity and insufficient patient stratification. In this review, we systematically synthesize current evidence on how chemokine networks regulate key TIME component (macrophages, T cells, cancer-associated fibroblasts, myeloid-derived suppressor cells, and cancer stem cells) to drive TNBC progression, metastasis, and therapeutic resistance. We also critically evaluate chemokine-targeted interventions, spanning preclinical candidates (small-molecule inhibitors, monoclonal antibodies, miRNA-based therapies, natural products, and nanocarrier systems) to clinical-stage agents. A critical gap emerges from this evaluation: although numerous chemokine axes demonstrate robust preclinical efficacy, most clinical trials have yielded negative or marginal results. These failures are largely attributable to target redundancy, the absence of subtype-specific biomarkers, and suboptimal combination strategies. Based on recent research advances, we propose a three-pillar framework for future therapeutic success: precision subtyping-guided target selection, rational combination regimens (particularly with immune checkpoint inhibitors), and iterative biomarker validation. Overall, this review provides a roadmap for navigating chemokine network complexity, distilling actionable insights for clinical translation, and defining priority research directions to overcome current bottlenecks in TNBC chemokine-targeted therapy.
Wanyu Wang, Linhua Chen, Wei Guo et al.· Frontiers in Immunology· 0 citations
Small cell lung cancer (SCLC) is an aggressive malignancy with limited treatment options, and the integration of immune checkpoint inhibitors (ICIs) into treatment regimens has reshaped the therapeutic landscape. However, challenges such as rapid resistance and lack of effective predictive biomarkers remain. This review highlights the pivotal roles of biomarkers in SCLC, underscoring their contributions to treatment resistance across tumor-intrinsic mechanisms, immune landscape of the tumor microenvironment (TME) and systemic host factors. Tumor-intrinsic features, including molecular subtypes, genetic alterations such as TP53 and RB1 mutations, and tumor mutation burden (TMB), have shown varying associations with ICI efficacy. Notably, the SCLC-I (inflamed) molecular subtype appears more responsive to immunotherapy. Within the TME, programmed cell death ligand 1 expression, tumor-infiltrating lymphocytes (TILs), regulatory T cells, myeloid-derived suppressor cells, and tissue-associated cytokines and chemokines contribute to immune modulation. High CD8+ TILs are linked to better outcomes, while increased immunosuppressive populations often suppress anti-tumor response. Systemic factors, encompassing both tumor-derived (ctDNA, CTCs, tumor-derived EVs) and host-derived (circulating immune cell phenotypes, MHC expression, immune profile, baseline clinical characteristics) components, provide valuable insights into treatment response and prognosis. Further research is needed to validate biomarkers and investigate combination approaches to overcome resistance, offering hope for improved patient outcomes in SCLC.
Shuxing Wang, Xin-rui Zhao, Yue-yue Zeng et al.· Critical reviews in oncology...· 0 citations
This review provides a framework for understanding and overcoming immunotherapy resistance, advancing the paradigm from "effective" to "precise" immuno-oncology in breast cancer.
Jia-Mei Wang, Yi Zhou, Fei-Fei Li et al.· Critical reviews in oncology...· 0 citations
Triple-negative breast cancer remains an aggressive and biologically heterogeneous breast cancer subtype. Although the therapeutic landscape has expanded, durable disease control remains clinically challenging in many settings. Existing reviews often organize TNBC therapy by drug class or molecular subtype, which can obscure how treatment response is shaped by interacting biological layers. Here, we review current and emerging therapeutic strategies through a three-layer framework: tumor-cell-intrinsic vulnerabilities, the local immune and stromal microenvironment, and host-level systemic modifiers. We summarize established approaches, including chemotherapy, immune checkpoint blockade, antibody–drug conjugates and PARP inhibition in biomarker-defined settings, and distinguish them from maturing or exploratory strategies such as pathway-directed therapy, epigenetic modulation, anti-vascular combinations, regulated cell-death induction, cellular therapy, vaccines, microbiome-related interventions, liquid biopsy, AI-supported multiomics and adaptive trial designs. This framework integrates evidence level, disease stage, biomarker reliability and patient tolerance into treatment selection for TNBC precision therapy.
Zi-Xun Wang, Xi-Yu Liu, Yu-Xiao Wu et al.· Journal of Hematology & Onco...· 0 citations
Breast cancer (BC) remains the leading cause of cancer-related mortality and a major contributor to disease burden among women worldwide. Although PD‑1/PD‑L1‑targeting immune checkpoint inhibitors have become a standard treatment for certain triple‑negative breast cancer subgroups, their use across the broader BC population is limited by intrinsic resistance, an immunosuppressive tumor microenvironment (TME), and treatment‑related adverse effects. The present review offers a comprehensive synthesis of the immunotherapeutic paradigm in BC, spanning ICIs, adoptive cellular therapies (CAR-T, CAR-NK, CAR-M, TIL, TCR-T, and CIK cells), and emerging immune modulators. We critically evaluate pivotal clinical trials, discuss cross-cutting challenges—including biomarker development, therapy resistance, and the practical limitations of cellular products—and highlight rational combinatorial strategies. By contrasting the translational readiness of diverse modalities and outlining a framework for personalized therapy, this review aims to inform future research and clinical practice in harnessing immunity against BC.
Ali Mussa, Mahasin Hamid, M. Talib et al.· Journal of Translational Med...· 0 citations
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