MINI REVIEW article
Front. Oncol.
Sec. Cancer Immunity and Immunotherapy
Volume 15 - 2025 | doi: 10.3389/fonc.2025.1618903
This article is part of the Research TopicNanotechnology-Based Delivery Systems for Cancer TreatmentView all 8 articles
Research Advances in Immune Agonists and Their Nanoparticles for Enhancing the Immunotherapeutic Efficacy of PD-1 Inhibitors in Malignancies
Provisionally accepted
Renjie Xia1,2Juan Liang3Jianguo Ma2,4
Xiaoyu Du1,2Liangbin Ma1,2Xiongxiong Han2,4Yong Wang2,4Jianwei Qin2*
Long Yan2*- 1Department of Medicine, Northwest Minzu University, Lanzhou, China
- 2Department of Hepatobiliary Surgery, The 940th Hospital of Joint Logistic Support Force of Chinese People’s Liberation Army, lanzhou, China
- 3Intensive Care Units, 940th Hospital, Joint Logistics Support Force of the People's Liberation Army, Lanzhou, China
- 4First School of Clinical Medicine, Gansu University of Chinese Medicine, Lanzhou, China
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Immune checkpoint blockade (ICB), particularly targeting programmed cell death-1 (PD-1), has revolutionized cancer immunotherapy but remains limited by heterogeneous therapeutic responses and immune-related toxicities. This review systematically examines the integration of immune agonists-STING, TLR, CD40, and OX40 agonists-with PD-1 inhibitors to overcome resistance and amplify antitumor immunity. Nanoparticle delivery systems emerge as transformative platforms, addressing critical limitations of free agonists, including enzymatic degradation, off-target toxicity, and poor pharmacokinetics. By leveraging tunable physicochemical properties (e.g., size, surface charge, stimuli-responsive release), nanoparticles enhance tumor-specific accumulation, prolong agonist half-life, and synergize with PD-1 inhibitors to remodel immunosuppressive microenvironments. Preclinical and early clinical studies demonstrate combinatorial strategies achieving increases in T cell infiltration and enhancements in anti-angiogenic activity compared to monotherapies. However, translational challenges persist, including nanoparticle-induced immunotoxicity (ROS-mediated inflammation), manufacturing scalability hurdles, and interspecies discrepancies in murine models. Future directions emphasize personalized nanovaccines, supramolecular cytosolic delivery systems (e.g., Calix-STING), and biomarker-driven trials to optimize efficacy in advanced pancreatic, melanoma, and immunologically quiescent tumors. This work underscores the imperative for interdisciplinary collaboration to standardize nanoparticle design and clinical validation frameworks, ultimately bridging the gap between nanomedicine innovation and oncology practice.
Keywords: immune agonists, PD-1 inhibitors, nanoparticle delivery systems, Tumor immunotherapy, Combinatorial therapy, Immunotoxicity
Received: 27 Apr 2025; Accepted: 31 Jul 2025.
Copyright: © 2025 Xia, Liang, Ma, Du, Ma, Han, Wang, Qin and Yan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Jianwei Qin, Department of Hepatobiliary Surgery, The 940th Hospital of Joint Logistic Support Force of Chinese People’s Liberation Army, lanzhou, China
Long Yan, Department of Hepatobiliary Surgery, The 940th Hospital of Joint Logistic Support Force of Chinese People’s Liberation Army, lanzhou, China
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