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Pharmaceutics
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Nanomedicines for Overcoming Tumor Immunotherapy Tolerance
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Nanomedicines for Overcoming Tumor Immunotherapy Tolerance

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Nanomedicine and Nanotechnology".

Deadline for manuscript submissions: 31 January 2026 | Viewed by 7638

Special Issue Editor

Prof. Dr. Yaping Li

grade E-Mail Website
Guest Editor
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Interests: nanoformulations; innovative drug delivery technologies

Special Issue Information

Dear Colleagues,

Immunotherapy, boosting natural defenses against cancer, has revolutionized the field of oncology and yielded considerable clinical benefits. However, tumors can develop tolerance to immunotherapy via multiple mechanisms such as decreasing antigen presentation, secreting immunosuppressive factors, recruiting immunosuppressive cell populations and upregulating negative regulatory pathways. Primary, adaptive and acquired forms of resistance enable tumors to evade immune surveillance and killing, significantly limiting the outcome of immunotherapy.

With the advantages of controllable delivery features and multidrug delivery ability, nanomedicines are widely harnessed to achieve safe and effective immunotherapy. Various strategies based on nanomedicines aiming to overcome immunotherapy tolerance have been developed and have received widespread attention such as by inducing the immunogenetic cell death of tumors, regulating intra-tumoral immune cell populations and modulating cytokines. This Special Issue contains research articles and reviews focusing on the development of novel strategies based on nanotechnology for combating tumor immunotherapy tolerance.

Nanomedicine-based tumor immunotherapy, as a pivotal cross-discipline associated with the fields of immunology, oncology and material sciences, has the potential to advance the clinical applicability and outcomes of immunotherapy to a new stage. The successful publication of this Special Issue will promote the research in the field of nanomedicine-based tumor immunotherapy and has significant scientific value.

Prof. Dr. Yaping Li
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • tumor immunotherapy
  • immunotherapy tolerance
  • nanomedicine

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Published Papers (5 papers)

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Review

32 pages, 1691 KiB  
Review
Aptamers Targeting Immune Checkpoints for Tumor Immunotherapy
by Amir Mohammed Abker Abdu, Yanfei Liu, Rami Abduljabbar, Yunqi Man, Qiwen Chen and Zhenbao Liu
Pharmaceutics 2025, 17(8), 948; https://doi.org/10.3390/pharmaceutics17080948 - 22 Jul 2025
Viewed by 489
Abstract
Tumor immunotherapy has revolutionized cancer treatment by harnessing the immune system to recognize and eliminate malignant cells, with immune checkpoint inhibitors targeting programmed death receptor 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) demonstrating remarkable clinical success. However, challenges such [...] Read more.
Tumor immunotherapy has revolutionized cancer treatment by harnessing the immune system to recognize and eliminate malignant cells, with immune checkpoint inhibitors targeting programmed death receptor 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) demonstrating remarkable clinical success. However, challenges such as treatment resistance, immune-related adverse effects, and high costs highlight the need for novel therapeutic approaches. Aptamers, short, single-stranded oligonucleotides with high specificity and affinity for target molecules, have emerged as promising alternatives to conventional antibody-based therapies. This review provides a comprehensive analysis of aptamer-based strategies targeting immune checkpoints, with a particular focus on PD-1/PD-L1 and CTLA-4. We summarize recent advances in aptamer design, including bispecific and multifunctional aptamers, and explore their potential in overcoming immune resistance and improving therapeutic efficacy. Additionally, we discuss strategies to enhance aptamer stability, bioavailability, and tumor penetration through chemical modifications and nanoparticle conjugation. Preclinical and early clinical studies have demonstrated that aptamers can effectively block immune checkpoint pathways, restore T-cell activity, and synergize with other immunotherapeutic agents to achieve superior anti-tumor responses. By systematically reviewing the current research landscape and identifying key challenges, this review aims to provide valuable insights into the future directions of aptamer-based cancer immunotherapy, paving the way for more effective and personalized treatment strategies. Full article
(This article belongs to the Special Issue Nanomedicines for Overcoming Tumor Immunotherapy Tolerance)
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Graphical abstract

32 pages, 2894 KiB  
Review
Extracellular Vesicle-Based Strategies for Tumor Immunotherapy
by Luksika Jiramonai, Xing-Jie Liang and Mengliang Zhu
Pharmaceutics 2025, 17(2), 257; https://doi.org/10.3390/pharmaceutics17020257 - 14 Feb 2025
Cited by 2 | Viewed by 1123
Abstract
Immunotherapy is one of the most promising approaches for cancer management, as it utilizes the intrinsic immune response to target cancer cells. Normally, the human body uses its immune system as a defense mechanism to detect and eliminate foreign objects, including cancer cells. [...] Read more.
Immunotherapy is one of the most promising approaches for cancer management, as it utilizes the intrinsic immune response to target cancer cells. Normally, the human body uses its immune system as a defense mechanism to detect and eliminate foreign objects, including cancer cells. However, cancers develop a ‘switch off’ mechanism, known as immune checkpoint proteins, to evade immune surveillance and suppress immune activation. Therefore, significant efforts have been made to develop the strategies for stimulating immune responses against cancers. Among these, the use of extracellular vesicles (EVs) to enhance the anti-tumor immune response has emerged as a particularly promising approach in cancer management. EVs possess several unique properties that elevate the potency in modulating immune responses. This review article provides a comprehensive overview of recent advances in this field, focusing on the strategic usage of EVs to overcome tumor-induced immune tolerance. We discuss the biogenesis and characteristics of EVs, as well as their potential applications in medical contexts. The immune mechanisms within the tumor microenvironment and the strategies employed by cancers to evade immune detection are explored. The roles of EVs in regulating the tumor microenvironment and enhancing immune responses for immunotherapy are also highlighted. Additionally, this article addresses the challenges and future directions for the development of EV-based nanomedicine approaches, aiming to improve cancer immunotherapy outcomes with greater precision and efficacy while minimizing off-target effects. Full article
(This article belongs to the Special Issue Nanomedicines for Overcoming Tumor Immunotherapy Tolerance)
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Figure 1

22 pages, 5277 KiB  
Review
Drug Delivery Systems Based on Metal–Organic Frameworks for Tumor Immunotherapy
by Ning Yang, Zongyan He and Tianqun Lang
Pharmaceutics 2025, 17(2), 225; https://doi.org/10.3390/pharmaceutics17020225 - 10 Feb 2025
Cited by 1 | Viewed by 1382
Abstract
Metal–organic frameworks (MOFs) are a class of inorganic-organic hybrid nanoparticles formed by the coordination of metal ions/clusters and organic ligands. Due to their high porosities, large surface areas, adjustable structures, and responsiveness to light/sound, etc., MOFs have shown great clinical potential in the [...] Read more.
Metal–organic frameworks (MOFs) are a class of inorganic-organic hybrid nanoparticles formed by the coordination of metal ions/clusters and organic ligands. Due to their high porosities, large surface areas, adjustable structures, and responsiveness to light/sound, etc., MOFs have shown great clinical potential in the field of tumor therapy. Tumor immunotherapy exerts antitumor effects through reshaping tumor immune microenvironment, showing significant preclinical and clinical advantages. Based on the mechanisms of immunity activation, the tumor immunotherapy agents can be divided into chemotherapeutic agents, immunomodulators, enzymes, tumor vaccines and oligonucleotide drugs, etc. Herein, we review the MOFs-based drug delivery systems for tumor immunotherapy. The classification of MOFs, followed by their antitumor immunity activation mechanisms, are first introduced. Drug delivery systems based on MOFs with different immunotherapy agents are also summarized, especially the synergetic immunity activation mechanisms triggered by MOFs and their loadings. Furthermore, the merits and drawbacks of MOFs and the potential strategies for MOFs to promote their clinical applications are discussed. Full article
(This article belongs to the Special Issue Nanomedicines for Overcoming Tumor Immunotherapy Tolerance)
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Graphical abstract

23 pages, 2778 KiB  
Review
Self-Tumor Antigens in Solid Tumors Turned into Vaccines by α-gal Micelle Immunotherapy
by Uri Galili
Pharmaceutics 2024, 16(10), 1263; https://doi.org/10.3390/pharmaceutics16101263 - 27 Sep 2024
Cited by 1 | Viewed by 2019
Abstract
A major reason for the failure of the immune system to detect tumor antigens (TAs) is the insufficient uptake, processing, and presentation of TAs by antigen-presenting cells (APCs). The immunogenicity of TAs in the individual patient can be markedly increased by the in [...] Read more.
A major reason for the failure of the immune system to detect tumor antigens (TAs) is the insufficient uptake, processing, and presentation of TAs by antigen-presenting cells (APCs). The immunogenicity of TAs in the individual patient can be markedly increased by the in situ targeting of tumor cells for robust uptake by APCs, without the need to identify and characterize the TAs. This is feasible by the intra-tumoral injection of α-gal micelles comprised of glycolipids presenting the carbohydrate-antigen “α-gal epitope” (Galα1-3Galβ1-4GlcNAc-R). Humans produce a natural antibody called “anti-Gal” (constituting ~1% of immunoglobulins), which binds to α-gal epitopes. Tumor-injected α-gal micelles spontaneously insert into tumor cell membranes, so that multiple α-gal epitopes are presented on tumor cells. Anti-Gal binding to these epitopes activates the complement system, resulting in the killing of tumor cells, and the recruitment of multiple APCs (dendritic cells and macrophages) into treated tumors by the chemotactic complement cleavage peptides C5a and C3a. In this process of converting the treated tumor into a personalized TA vaccine, the recruited APC phagocytose anti-Gal opsonized tumor cells and cell membranes, process the internalized TAs and transport them to regional lymph-nodes. TA peptides presented on APCs activate TA-specific T cells to proliferate and destroy the metastatic tumor cells presenting the TAs. Studies in anti-Gal-producing mice demonstrated the induction of effective protection against distant metastases of the highly tumorigenic B16 melanoma following injection of natural and synthetic α-gal micelles into primary tumors. This treatment was further found to synergize with checkpoint inhibitor therapy by the anti-PD1 antibody. Phase-1 clinical trials indicated that α-gal micelle immunotherapy is safe and can induce the infiltration of CD4+ and CD8+ T cells into untreated distant metastases. It is suggested that, in addition to converting treated metastases into an autologous TA vaccine, this treatment should be considered as a neoadjuvant therapy, administering α-gal micelles into primary tumors immediately following their detection. Such an immunotherapy will convert tumors into a personalized anti-TA vaccine for the period prior to their resection. Full article
(This article belongs to the Special Issue Nanomedicines for Overcoming Tumor Immunotherapy Tolerance)
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Figure 1

22 pages, 4614 KiB  
Review
Biomimetic Nucleic Acid Drug Delivery Systems for Relieving Tumor Immunosuppressive Microenvironment
by Wenlu Yan, Ying Cao, Qi Yin and Yaping Li
Pharmaceutics 2024, 16(8), 1028; https://doi.org/10.3390/pharmaceutics16081028 - 1 Aug 2024
Viewed by 1832
Abstract
Immunotherapy combats tumors by enhancing the body’s immune surveillance and clearance of tumor cells. Various nucleic acid drugs can be used in immunotherapy, such as DNA expressing cytokines, mRNA tumor vaccines, small interfering RNAs (siRNA) knocking down immunosuppressive molecules, and oligonucleotides that can [...] Read more.
Immunotherapy combats tumors by enhancing the body’s immune surveillance and clearance of tumor cells. Various nucleic acid drugs can be used in immunotherapy, such as DNA expressing cytokines, mRNA tumor vaccines, small interfering RNAs (siRNA) knocking down immunosuppressive molecules, and oligonucleotides that can be used as immune adjuvants. Nucleic acid drugs, which are prone to nuclease degradation in the circulation and find it difficult to enter the target cells, typically necessitate developing appropriate vectors for effective in vivo delivery. Biomimetic drug delivery systems, derived from viruses, bacteria, and cells, can protect the cargos from degradation and clearance, and deliver them to the target cells to ensure safety. Moreover, they can activate the immune system through their endogenous activities and active components, thereby improving the efficacy of antitumor immunotherapeutic nucleic acid drugs. In this review, biomimetic nucleic acid delivery systems for relieving a tumor immunosuppressive microenvironment are introduced. Their immune activation mechanisms, including upregulating the proinflammatory cytokines, serving as tumor vaccines, inhibiting immune checkpoints, and modulating intratumoral immune cells, are elaborated. The advantages and disadvantages, as well as possible directions for their clinical translation, are summarized at last. Full article
(This article belongs to the Special Issue Nanomedicines for Overcoming Tumor Immunotherapy Tolerance)
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