---
title: "Polymer-Based Drug Delivery Targeting the Tumor Microenvironment for Immunotherapy of Triple-Negat"
id: "frontiers-in-immunology-14-advancements-in-polymer-based-drug-delivery-systems-targeting-the-tumor"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-14-advancements-in-polymer-based-drug-delivery-systems-targeting-the-tumor"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1927103"
published_at: "2026-09-23T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Polymer-Based Drug Delivery Targeting the Tumor Microenvironment for Immunotherapy of Triple-Negat
## Provenance & Clinical Metadata
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- **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.2026.1927103)
- **Published At:** 2026-09-23T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- Source: Frontiers in Immunology article page for an article on **polymer-based drug delivery**, the **tumor microenvironment**, and **immunotherapy** for **triple-negative breast cancer**. The page content available to this tool contains site navigation, journal sections, and repeated website header material only. - The source as provided does not include the article abstract, methods, results, discussion, figures, numerical data, author names, affiliations, or conclusions. Specific experimental details, outcomes, and recommendations were not reported in the source content available here. - No clinical or preclinical findings, safety data, or therapeutic recommendations are present in the supplied page content. No study endpoints, sample sizes, or statistical results were retrievable from the source text. - The only verifiable metadata from the supplied source is the journal name (Frontiers in Immunology) and the thematic focus inferred from the original title. Other bibliographic details such as DOI are present in the URL but substantive article text is absent. - For clinicians or researchers seeking usable evidence, the source content is insufficient. Access to the full article or publisher-provided PDF is required to extract validated clinical or experimental information. - Actions recommended based on the available source: retrieve the full article from the journal site or institutional access, verify authorship and study design, and then re-evaluate clinical relevance using the complete report.
## Clinical Analysis & Structured Key Points
Frontiers | Advancements in polymer-based drug delivery systems targeting the tumor microenvironment for immunotherapy of triple-negative breast cancer REVIEW article Front. Immunol. , 23 September 2026 Sec. Cancer Immunity and Immunotherapy Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1927103 Published in Frontiers in Immunology Cancer Immunity and Immunotherapy 7 impact factor 11.3 citescore Editor & Reviewers Edited by D A Dr Asgar Ali Reviewed by J Y Jun Ye W P Wanbing Pan Y M Yijun Mei Outline Figures and Tables Figure 1 View in article Figure 2 View in article Figure 3 View in article Figure 4 View in article Figure 5 View in article Figure 6 View in article Table 1 Recent high-quality polymer-based systems for enhancing tumor immune response and antigen presentation in breast cancer/TNBC. View in article Table 2 Recent high-quality polymer-based systems targeting stromal and ECM barriers in TNBC. View in article Table 3 Recent high-quality polymeric delivery systems targeting immunosuppressive cellular components in breast cancer/TNBC. View in article Table 4 Recent high-quality polymeric delivery systems for metabolic and hypoxia-responsive TME reprogramming in breast cancer/TNBC. View in article Table 5 Subtype- and TME-informed considerations for PBDS design in TNBC. View in article REVIEW article Front. Immunol. , 23 September 2026 Sec. Cancer Immunity and Immunotherapy Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1927103 Advancements in polymer-based drug delivery systems targeting the tumor microenvironment for immunotherapy of triple-negative breast cancer Z W Zhenxiao Wang 1 M L Mo Li 2 Z W Zhenyu Wang 3 Y W Ying Wang 3 * 1. Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, Jilin, China 2. Department of Thyroid Surgery, The Second Hospital of Jilin University, Changchun, Jilin, China 3. Department of Breast Surgery, The Second Hospital of Jilin University, Changchun, Jilin, China See more Article metrics View details Abstract Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by high invasiveness, frequent recurrence, and metastasis, along with limited targeted therapeutic options. Despite clinical advances achieved with immune checkpoint inhibitors, poly(ADP-ribose) polymerase (PARP) inhibitors, and antibody-drug conjugates, the complex immunosuppressive tumor microenvironment (TME) of TNBC hinders drug delivery and compromises the efficacy of immunotherapy. Multiple adverse features of the TME, including impaired tumor immunogenicity, dysfunctional antigen presentation, dense extracellular matrix barriers, abundant immunosuppressive cell populations, metabolic reprogramming, hypoxia, and acidification, collectively contribute to immunotherapy resistance. Polymer-based drug delivery systems (PBDS), with tunable physicochemical properties, structural versatility, high drug-loading capacity, and responsiveness to TME-associated stimuli, have emerged as promising platforms for remodeling the TNBC TME. These polymeric carriers can achieve tumor enrichment, enable controlled release, improve deep tissue penetration, and facilitate co-delivery of multiple therapeutic agents to exert synergistic effects. In this review, we adopt a barrier-to-design framework that directly links the major immunosuppressive barriers of the TNBC TME to corresponding polymer-engineering strategies. Unlike carrier-centered reviews that primarily catalog nanomaterial classes, we critically compare stimuli-responsive activation, sequential release, biomimetic targeting, local hydrogel depots, spatial targeting and multifunctional co-delivery according to their mechanistic rationale, preclinical evidence, model dependence, safety and translational feasibility. We further discuss subtype- and biomarker-informed patient selection, design requirements for primary tumors, tumor-draining lymph nodes and metastatic niches, and the need to balance multifunctionality against manufacturability. This framework provides a clinically oriented roadmap for developing barrier-matched PBDS as rational partners for TNBC immunotherapy. Graphical Abstract Barrier-matched polymer engineering for TNBC immunotherapy. Major immune, stromal and metabolic barriers in the TNBC TME are matched to modular PBDS strategies—including smart polymer nanoparticles, biomimetic coatings, local hydrogels and stimuli-responsive release—to drive TME remodeling, enhance checkpoint-blockade sensitivity and reduce recurrence/metastasis. Biomarker selection, spatial targeting, biosafety and manufacturability act as translational filters. 1 Introduction Triple-negative breast cancer (TNBC) represents one of the most aggressive and heterogeneous molecular subtypes of breast cancer. It is defined by the absence of expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) and accounts for approximately 15%–20% of all breast cancer cases ( 1 ). Compared to hormone receptor-positive (HR + ) or HER2-positive breast cancer, TNBC is more prevalent among younger patients. Moreover, it is associated with clinical features such as high histological grade, active proliferation, early recurrence, and an elevated risk of visceral and brain metastases ( 2 ). Recent advances in understanding TNBC molecular typing, immune microenvironment characteristics, and drug-targetable pathways have transformed TNBC from a “target-free” disease into a complex disease spectrum. These include strategies targeting immune pathways, DNA damage repair mechanisms, trophoblast cell-surface antigen 2 (TROP2), epidermal growth factor receptor (EGFR), and metabolic pathways ( 3 , 4 ). Significant progress has recently been achieved in TNBC therapy. Integrating immune checkpoint inhibitors (ICIs), such as pembrolizumab, with chemotherapy has emerged as a pivotal treatment strategy for patients with high-risk early-stage TNBC and PD-L1-positive metastatic TNBC ( 5 ). Additionally, PARP inhibitors are approved for patients with HER2-negative breast cancer who possess germline breast cancer susceptibility gene 1/2 (BRCA1/2) mutations. Moreover, antibody-drug conjugates (ADCs), including sacituzumab govitecan and certain HER2-low-related ADCs, offer novel therapeutic options for refractory TNBC ( 6 ). However, these advances also indicate that TNBC cannot be effectively managed solely through systemic drug delivery or through a single immune checkpoint blockade (ICB). The primary challenge in treating TNBC lies in its complex and dynamically evolving tumor microenvironment (TME). This environment comprises various components, including tumor cells, tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), dendritic cells (DCs), regulatory T cells (Tregs), cancer-associated fibroblasts (CAFs), vascular cells, the extracellular matrix (ECM), as well as various cytokines, chemokines, and metabolites ( 7 ). Collectively, these components contribute to the limited efficacy of therapeutic interventions such as ICIs, cell therapy, and tumor vaccines by fostering an “immune cold” phenotype. This phenotype is characterized by impaired antigen presentation, depletion of effector T cells, aggregation of immunosuppressive cells, and the establishment of physical and metabolic barriers ( 8 ). Although TNBC generally exhibits higher immune infiltration and immunogenicity than certain HR+ breast cancers, many TNBC tumors nevertheless display an inflamed but dysfunctional or immune-excluded phenotype. This phenotype is characterized by PD-L1 upregulation, T-cell dysfunction, myeloid suppression, fibrotic barriers, and metabolic immunosuppression ( 7 , 9 , 10 ). Hypoxia, acidic pH, lactic acid accumulation, and redox imbalance further impair the function of CD8 + T cells and natural killer (NK) cells, thereby facilitating tumor cell survival, invasion, and metastasis ( 11 ). Furthermore, tumor-draining lymph nodes (TDLNs) and distant pre-metastatic niches can be reprogrammed into immunosuppressive states by TNBC, thereby compromising systemic antitumor immunity ( 12 ). Emerging evidence also suggests that the gut microbiome plays a role in estrogen metabolism, regulation of the inflammatory state, immune modulation, and therapeutic response in TNBC ( 13 – 15 ). To precisely target the TME and address the aforementioned challenges, polymer-based drug delivery systems (PBDS) offer several distinct advantages, including tunable physicochemical properties, controlled release, facile surface modification, and responsiveness to TME stimuli ( 16 ). Unlike conventional small-molecule therapeutics that typically target a single pathway, polymeric nanocarriers—including nanoparticles, micelles, hydrogels, and related platforms—enable the co-delivery of chemotherapeutic agents, ICIs, cytokines, and immune adjuvants. Polymeric architectures discussed in this review include nanoparticles, micelles, polymer conjugates, nanogels and injectable/local hydrogels. Importantly, these formats should not be selected as isolated material categories; rather, their physicochemical properties and route of administration should be matched to the dominant biological barrier, desired spatial distribution and release sequence ( 17 ). Polymeric carriers may exploit enhanced permeability and retention (EPR)-mediated passive accumulation in some tumors; however, the magnitude and reproducibility of the EPR effect are highly heterogeneous and are generally less predictable in patients than in many preclinical models. Active targeting and stimuli-responsive designs may improve cellular uptake, retention, or site-specific payload release after systemic exposure, but they should be regarded as complementary strategies rather than substitutes for rigorous pharmacokinetic, biodistribution, and safety evaluation ( 18 – 21 ). Recent advancements in nanotechnology-based TNBC immunotherapy approaches have demonstrated their potential to synergistically enhance ICI efficacy, reprogram CAFs, modulate TAM polarization, and remodel the local immune microenvironment. These findings provide a novel strategy for overcoming the limitations of traditional therapies ( 16 ). PBDS designed for the TNBC TME have evolved from systems focused mainly on tumor accumulation to platforms that can also modulate immune, stromal, and metabolic features ( 22 ). Important barriers to translation remain, including carrier instability during systemic circulation, protein-corona-mediated clearance, inconsistent performance across preclinical models, TNBC heterogeneity, and the limited availability of models that reproduce human immunity ( 23 , 24 ). Recent reviews have addressed nanomaterial-based TNBC therapy, the breast cancer TME, or polymeric nanomedicine across tumor types. Here, we instead organize the field around the TME barrier being addressed and examine how polymer design is adapted to that barrier. Representative systems are compared with respect to design, biological target, preclinical limitations, and translational feasibility, with particular attention to their integration with established TNBC therapies. 2 Immunosuppressive mechanisms in the TNBC TME Although these processes are discussed separately for clarity, the TNBC TME is shaped by a coupled network of immunological, stromal and metabolic barriers rather than by isolated defects. Heterogeneous and often insufficient effective immunogenicity limits productive tumor-specific T-cell responses; defective dendritic-cell recruitment and maturation further compromises antigen cross-presentation; CAF-driven ECM remodeling creates a spatial barrier to immune-cell trafficking and drug penetration; TAMs, MDSCs, Tregs and suppressive CAF subsets reinforce inhibitory cytokine and nutrient-depletion circuits; and hypoxia, acidosis, lactate accumulation and lipid-metabolic rewiring progressively impair effector lymphocyte function. These layers interact bidirectionally—for example, hypoxia and lactate promote myeloid suppression, whereas CAF-rich stroma worsens perfusion and metabolic stress—thereby stabilizing immune-excluded and therapy-resistant states. Figure 1 summarizes these interconnected barriers and provides the biological basis for the barrier-matched polymer design strategies discussed in Section 3. Figure 1 Immunosuppressive mechanisms within the TME of TNBC. The TNBC TME is governed by multiple interconnected immunosuppressive mechanisms that collectively impair antitumor immunity and limit the efficacy of ICIs. Low TMB, limited neoantigen generation, insufficient CD8 + T-cell infiltration, and weak immune activation contribute to an “immune-cold” phenotype. DC dysfunction, characterized by impaired recruitment, maturation, antigen cross-presentation, MHC expression, and CD80/CD86-mediated costimulation, further compromises T-cell priming. CAF-driven ECM remodeling increases stromal stiffness and interstitial pressure, thereby restricting CD8 + T-cell infiltration and drug penetration. In parallel, TAMs, MDSCs, Tregs, and CAFs establish an immunosuppressive cellular network through IL-10, TGF-β, ROS, nutrient depletion, PD-1/PD-L1 signaling, and myeloid-mediated suppression, ultimately promoting T-cell exhaustion. Metabolic reprogramming, lactate accumulation, acidic pH, lipid metabolic alterations, FAO, hypoxia, and HIF-1α activation further suppress CD8 + T-cell and NK-cell function. Together, these mechanisms drive immune exclusion, sustain an immunosuppressive TME, and contribute to ICI resistance in TNBC. 2.1 Deficiency in tumor immunogenicity and the ‘immune cold’ phenotype Although TNBC is often considered one of the more immunogenic subtypes of breast cancer, it is still characterized by overall limited immunogenicity and a weakly inflamed TME, which remain major barriers to effective immunotherapy. In contrast to highly mutated “hot” tumors such as melanoma and non-small cell lung cancer, TNBC exhibits a relatively low tumor mutational burden (TMB) and contains only a limited subset of tumor cell populations capable of generating immunogenic neoantigens that can drive robust adaptive immune responses ( 25 ). Multiple studies have failed to demonstrate a consistent correlation between neoantigen load and CD8 + T cell infiltration in breast cancer, thereby undermining the neoantigen-driven T cell response hypothesis. A comprehensive pan-cancer analysis by McGrail et al. further supports this observation. In the TMB-high (TMB-H) subgroup of breast cancer, the objective response rate (ORR) to ICB was only 15.3%, even lower than that observed in TMB-low (TMB-L) tumors, and was associated with poorer overall survival (OS). Notably, in the metastatic TNBC subgroup, none of the 10 TMB-H tumors responded to ICB, whereas the ORR in TMB-L tumors reached 20.5% ( 26 ). These findings indicate that TMB-H status alone is insufficient to predict effective neoantigen-driven antitumor immunity and represents a key limitation underlying the suboptimal clinical benefit of ICB in TNBC. Supporting this view, Vougiouklakis et al. performed a detailed genomic characterization of 527 TMB-H (≥10 mut/Mb) breast cancer cases. They demonstrated that, although the TNBC subtype exhibited the highest degree of immune cell infiltration among TMB-H tumors, overall TMB in breast cancer remained substantially lower than that observed in melanoma or lung cancer. While apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like mutational signatures predominated in TMB-H tumors, concurrent loss-of-function alterations in AT-rich interaction domain 1A and phosphatase and tensin homolog (PTEN) were frequently associated with immune cell exclusion. Collectively, these genomic features were associated with persistently low ICB response rates (≤20%). This is further supported by clinical evidence, including the KEYNOTE-012 trial, which reported an ORR of only 18.5% with single-agent pembrolizumab in PD-L1-positive metastatic TNBC, as well as the modest survival benefits observed in IMpassion130 and the lack of significant benefit in IMpassion131 ( 27 ). Collectively, these data suggest that even in TMB-high TNBC, increased mutational load alone is insufficient to overcome the physical and immunosuppressive barriers within the TME, making TMB an unreliable standalone predictive biomarker for ICB efficacy. The immunologically “cold” phenotype of TNBC is a multifactorial state driven by coordinated immune dysregulation across the lymph node–tumor axis, fibrotic and immunological exclusion barriers, myeloid-mediated immunosuppression (including TAM and MDSC accumulation), and impaired antigen presentation. Consequently, approaches focused solely on enhancing tumor-cell immunogenicity are generally insufficient to restore effective antitumor immunity ( 28 ). Conversely, polymer-based delivery systems capable of precise spatiotemporal intervention at multiple key nodes within the TME offer greater promise for achieving meaningful “cold-to-hot” conversion in TNBC immunotherapy. These platforms can simultaneously induce ICD, enhance DC maturation and antigen presentation, reprogram TAM polarization toward an antitumor phenotype, relieve T-cell exclusion, and potentiate responses to ICB ( 29 , 30 ). By targeting the interconnected immunosuppressive networks that sustain immune evasion, even in relatively more immunogenic TNBC subtypes, TME-targeted approaches have the potential to overcome the limitations of current ICB-based strategies and improve clinical outcomes in this aggressive breast cancer subtype. 2.2 DC dysfunction and antigen presentation failure DCs are the central antigen-presenting cells that bridge innate and adaptive immunity. Their dysfunction and impaired antigen presentation represent a key mechanism limiting the establishment of effective antitumor immune responses in the TNBC TME ( 31 ). Under normal physiological conditions, DCs efficiently take up, process, and present tumor-associated antigens via major histocompatibility complex (MHC) molecules, while simultaneously delivering costimulatory signals and secreting key cytokines, such as interleukin (IL)-12. This coordinated process primes naïve T cells and initiates tumor-specific immune responses ( 32 ). In the TNBC TME, however, DCs frequently exhibit impaired recruitment, arrested maturation, reduced cross-presentation capacity, and decreased expression of costimulatory molecules such as CD80 and CD86. These deficiencies disrupt the antitumor immune cycle at its earliest stage. The TNBC TME is enriched with multiple immunosuppressive mediators, including lactate, vascular endothelial growth factor (VEGF), IL-10, transforming growth factor-β (TGF-β), and hypoxia, all of which collectively inhibit DC maturation, antigen processing, and presentation through multiple signaling pathways ( 25 , 33 ). Consequently, the activation of naïve T cells is either completely suppressed or restricted to low-affinity, ineffective responses. Compounding these DC-intrinsic impairments, cancer cells in TNBC frequently harbor intrinsic defects in antigen-processing machinery and exhibit downregulated MHC class I expression. These tumor-intrinsic alterations diminish direct antigen presentation to effector CD8 + T cells. Furthermore, these alterations reduce the pool of properly processed tumor antigens available for DC-mediated cross-presentation, further compromising efficient priming of cytotoxic CD8 + T cells. The synergistic action of DC dysfunction, tumor cell-intrinsic defects in antigen presentation, immunosuppressive cellular networks, ECM barriers, and metabolic reprogramming results in insufficient infiltration and activation of effector T cells. This precludes the formation of an inflamed (immunologically “hot”) TME. Although TNBC generally exhibits higher levels of tumor-infiltrating lymphocytes and PD-L1 expres
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