This review explores sequential nanoregulation strategies based on different types of TME, and describes how functionalized nanocarriers, such as stimulus-responsive polymers, liposomes, and biomimetic nanoparticles, can be used to detect changes in the microenvironment, and to precisely deliver drugs when needed.
Abstract
Immune checkpoint inhibitors, like PD-1/PD-L1 blockers, have revolutionized cancer treatment in recent years. However, these therapies still face many problems, such as low objective response rates and drug resistance, making clinical treatment very difficult. Numerous studies have demonstrated that the heterogeneity of the tumor microenvironment (TME), including various subtypes such as “cold tumors”, “hot tumors”, and “immune-rejecting tumors”, as well as complex immunosuppressive mechanisms, is a major factor leading to resistance to immunotherapy. Chemotherapy and radiotherapy can aid in treatment by inducing immunogenic cell death, but they often lead to PD-L1 upregulation, which causes treatment effects to vary over time and space and reduces their efficacy. Given their excellent biocompatibility, drug delivery capacity, and responsiveness to environmental factors, nanomaterials offer a novel opportunity to address this challenge. This review explores sequential nanoregulation strategies based on different types of TME, describes how functionalized nanocarriers, such as stimulus-responsive polymers, liposomes, and biomimetic nanoparticles, can be used to detect changes in the microenvironment, like pH, enzymes, and reactive oxygen species, and to precisely deliver drugs when needed. This will allow researchers to target key points of immune activation, thereby blocking immune checkpoint signaling. These specific strategies, which include antigen release, immune system activation, and blocking interventions, not only offer new approaches for overcoming PD-L1 resistance but also shed light on the challenges and opportunities associated with applying these strategies in clinical practice.
Bladder cancer is a highly prevalent malignant tumor in the urinary system worldwide, and the treatment has been long facing significant challenges. Immunotherapy represented by PD-1 (programmed death receptor-1)/PD-L1 (programmed death ligand-1) inhibitors and targeted therapies such as antibody-drug conjugates have already changed the landscape. However, the efficacy of a single drug is limited, and the problem of drug resistance is quite prominent. The combined treatment strategy, through the deep synergy of pharmacology and immunology, aims to overcome tumor heterogeneity and immunosuppressive microenvironments. It has become a core research direction in the treatment of bladder cancer. This review systematically elaborates the synergistic biological mechanisms by which targeted drugs induce immunogenic cell death, re-adjust the tumor immune microenvironment, and immune checkpoint inhibitors amplify and prolong the therapeutic effect. It focuses on elaborating the groundbreaking clinical evidence achieved by the "ADC + immunotherapy" approach, such as ennozumab combined with pembrolizumab, in advanced first-line and neoadjuvant treatments, and also summarizes the emerging methods including dual immunotherapy combinations, immunotherapy combined with other regulators, and oncolytic viruses. Furthermore, this article thoroughly examines the challenges that may arise from combined treatment, such as the complexity of drug resistance mechanisms and the optimization of drug toxicity management. Finally, a series of prospects were presented regarding future directions such as the development of drugs targeting new targets in the tumor microenvironment. This article aims to provide an academic reference for a comprehensive understanding of the current status and future prospects of targeted and immunotherapy combined strategies for bladder cancer.
Zong-Hua Wang· International Journal of Bio...· 0 citations
Cancer immunotherapy has revolutionized the landscape of cancer treatment, particularly through the development of immune checkpoint blockade (ICB) targeting the PD-1/PD-L1 axis. However, the therapeutic efficacy of these interventions is frequently hindered by the immunosuppressive tumor microenvironment (TME), which is characterized by hypoxia, poor immune cell infiltration, and impaired antigen presentation. To overcome these barriers, MP-GCZ has been developed as a self-oxygenating biomimetic nanomotor to synergistically reprogram the TME and enhance antitumor immune responses through integrated multimodal mechanisms. This nanosystem combines photothermal therapy (PTT), cuproptosis-induced immunogenic cell death (ICD), and localized immune checkpoint modulation to address the complex immunosuppressive network of the TME. By leveraging a metal-organic framework scaffold, MP-GCZ enables controlled delivery of therapeutic components that alleviate hypoxia, trigger immunogenic tumor cell death, and enhance adaptive immune responses. When activated by near-infrared irradiation, MP-GCZ enhances dendritic cell maturation, increases infiltration of cytotoxic T lymphocytes, thereby transforming immunologically "cold" tumors into inflamed, immunogenic environments. Preclinical studies demonstrate that this strategy effectively suppresses both primary tumor growth and distant metastases, driven by systemic antitumor immunity. MP-GCZ represents a promising comprehensive approach to overcoming TME-mediated resistance and may offer a valuable solution to enhance the clinical efficacy of cancer immunotherapy.
Xin-yu Gu, Sheng-Wei Shen, Yuting He et al.· Materials Today Bio· 0 citations
The tumor immune microenvironment (TIME), composed of tumor cells, immune/stromal cells, cytokines, and other components, plays a central role in determining tumor immunogenicity and response to therapy. The balance between effector T/NK cells and immunosuppressive populations such as regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and M2-like tumor-associated macrophages (TAMs) determines whether tumors remain “cold” or become “hot”. Triple-negative breast cancer (TNBC) remains challenging to treat because it lacks estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) targets and exhibits high heterogeneity. To address these limitations, tumor microenvironment (TME)-targeted nanocarriers have emerged as a promising strategy. By exploiting features such as hypoxia, acidity, redox imbalance, and abnormal vascular and mechanical cues, these systems enable prolonged circulation, active targeting, and stimulus-responsive release, thereby enhancing the efficacy of therapies such as immune checkpoint blockade. This review summarizes major nanoplatforms and therapeutic strategies, while highlighting translational barriers including TIME heterogeneity, enhanced permeability and retention (EPR) effect, and protein corona formation. Finally, this review explains why patient stratification should be incorporated into the future development of TNBC nano-immunotherapy and argues for simplified, reproducible nanocarrier designs to support clinically applicable precision treatment.
Xiaoya Dong, Fengxin Cui, Lei Wang et al.· Frontiers in Immunology· 0 citations
Abstract Malignant tumors remain one of the most serious challenges to global health. Although chemotherapy and targeted therapy are available treatment options, their effectiveness is often limited by the complexity of the tumor microenvironment (TME). In recent years, immunotherapy has demonstrated significant potential in harnessing the immune system to combat cancer. Polymeric nanoparticles (PNPs) have emerged as versatile platforms for cancer immunotherapy, offering favorable biocompatibility, tunable size, and surface functionalization for targeted delivery. In this review, we critically evaluate PNP design strategies, emphasizing stimuli-responsive release mechanisms that enable spatiotemporally controlled drug delivery within the TME, thereby enhancing efficacy and minimizing systemic toxicity. We further highlight PNP-enabled synergistic therapies, including photodynamic, chemodynamic, and sonodynamic therapies, that induce immunogenic cell death (ICD) and potentiate antitumor immunity, as well as PNP-based vaccines (RNA, peptide, and in situ) that activate dendritic cells (DCs) and cytotoxic T lymphocytes (CTLs). Nevertheless, the clinical translation of PNP-based therapies is constrained by multiple factors, including manufacturing scalability, emulsifier-related toxicity, rapid RES clearance, inherent immunogenicity, and the heterogeneity of the TME. By bridging material engineering with immunological barriers and translational challenges, this review provides a critical framework for designing next-generation PNP immunotherapies toward personalized cancer treatment.
Dong-Qi Li, Jia Hu, Ying-Shu Cui et al.· International Journal of Nan...· 0 citations
Immune checkpoint inhibitors (ICIs), particularly antibodies targeting PD-1/PD-L1 and CTLA-4, have reshaped the treatment landscape of lung cancers, most notably non-small cell lung cancer (NSCLC). Nevertheless, only a subset of patients achieve durable benefit due to primary and acquired resistance that arises from tumor-intrinsic factors (e.g., oncogenic drivers and adaptive signaling), tumor-extrinsic determinants in the tumor microenvironment (TME) (e.g., impaired T-cell infiltration and immunosuppressive myeloid populations), and the dynamic evolution of biomarkers. Accordingly, current clinical and translational efforts in lung cancer focus on rational combination strategies—ICIs with chemotherapy, radiotherapy, and targeted agents (including RTK- and KRAS-pathway inhibitors)—as well as alternative approaches that modulate antigen presentation, myeloid regulation, and cancer stemness. In this review, we define a lung cancer–centered scope and summarize (i) established and emerging ICI-based regimens in lung cancer, (ii) mechanisms of resistance relevant to NSCLC and SCLC, (iii) biomarker integration for patient selection and monitoring, and (iv) future directions to optimize efficacy and safety through combinatory and alternative immunotherapeutic strategies.
Junyoung Park, Choong‐Hwan Kwak, Yu-Chan Chang et al.· Frontiers in Immunology· 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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