---
title: "Tumor-Activated Prodrug Nanoparticles for Cancer Immunotherapy: Article metadata and availability"
id: "frontiers-in-immunology-6-recent-advances-in-tumor-activated-prodrug-nanoparticles-for-cancer"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-6-recent-advances-in-tumor-activated-prodrug-nanoparticles-for-cancer"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1968703"
published_at: "2026-09-24T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Tumor-Activated Prodrug Nanoparticles for Cancer Immunotherapy: Article metadata and availability
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/frontiers-in-immunology-6-recent-advances-in-tumor-activated-prodrug-nanoparticles-for-cancer
- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1968703)
- **Published At:** 2026-09-24T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The source provided is a Frontiers in Immunology web page referencing an article titled “Recent advances in tumor-activated prodrug nanoparticles for cancer immunotherapy.” - The page content included site navigation, journal information, and a list of journal sections but did not include the article text, abstract, data, results, or conclusions. - The site lists many relevant journal sections such as **Cancer Immunity and Immunotherapy**, Methods and New Technologies in Immunology, and Vaccines and Molecular Therapeutics. - Multiple frontiers navigation elements, author submission links, and links to journal pages were present; a direct article URL was shown but the article body was not present in the provided source content. - Because the article body and specific scientific details were not included in the provided source, no factual details about mechanisms, formulations, preclinical or clinical results, safety, or future directions for **tumor-activated prodrug nanoparticles** can be reported from this source. - To obtain the complete review contents and specific findings, the full article must be accessed via the journal’s site using the provided article URL or the journal’s article search tools. - All statements above are limited to what was visible in the supplied source; specific study outcomes, experimental methods, or recommendations were not reported in the supplied content.
## Clinical Analysis & Structured Key Points
Frontiers | Recent advances in tumor-activated prodrug nanoparticles for cancer immunotherapy REVIEW article Front. Immunol. , 24 September 2026 Sec. Cancer Immunity and Immunotherapy Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1968703 Published in Frontiers in Immunology Cancer Immunity and Immunotherapy 7 impact factor 11.3 citescore Editor & Reviewers Edited by F A Furkan Ayaz Reviewed by Y Z Yi Zhang J W Jun Wang 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 Figure 7 View in article Table 1 Summary of TME-responsive PDNPs for targeted cancer immunotherapy. View in article Table 2 Examples of IDO inhibitors in clinical trials. View in article Table 3 Examples of STING agonists in clinical trials. View in article REVIEW article Front. Immunol. , 24 September 2026 Sec. Cancer Immunity and Immunotherapy Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1968703 Recent advances in tumor-activated prodrug nanoparticles for cancer immunotherapy G W Guanran Wang 1 K D Kun Du 1 D S Dikai Sun 1 S T Shengyuan Tong 1 Y R Yi Ren 2 * H Z Huicong Zhou 3 * 1. China-Japan Union Hospital of Jilin University, Changchun, China 2. School of Clinical Medicine, Tsinghua University, Beijing, China 3. Key Laboratory and Engineering Laboratory of Lymphatic Surgery Jilin Province, China-Japan Union Hospital of Jilin University, Changchun, China See more Article metrics View details Abstract Numerous therapeutic agents have been demonstrated to initiate antitumor immune responses, thereby driving significant progress in cancer immunotherapy. However, clinical translation is severely limited by persistent challenges, including systemic toxicity, the immunosuppressive tumor microenvironment (TME), and low nanoparticle delivery efficiency. Tumor-activated prodrug nanoparticles (PDNPs) integrate prodrug chemistry with nanoscale delivery, enabling localized drug activation in response to tumor microenvironmental cues or exogenous stimuli. Therapeutic specificity is improved and off-target toxicity is mitigated by this strategy, providing a promising platform for safe and effective drug delivery. Consequently, these systems have attracted extensive research attention. In this review, the design strategies, release mechanisms, and immunotherapeutic applications of TME-responsive and exogenous stimulus-responsive PDNPs are systematically detailed, together with active-targeting and hybrid strategies that further improve tumor-selective delivery and activation. Beyond serving as delivery vehicles for immunomodulators, these PDNPs are utilized in synergy with chemotherapy, photothermal/photodynamic therapy, and sonodynamic therapy to trigger immunogenic cell death. Furthermore, dendritic cell maturation and T-cell infiltration are promoted, thereby remodeling the immune microenvironment, particularly when administered in combination with immune checkpoint inhibitors. Finally, the key challenges and considerations for the clinical translation of tumor-activated PDNPs are highlighted, with the aim of guiding further research progress. 1 Introduction Cancer represents a complex systemic disease with a multifactorial etiology, characterized primarily by malignant cell proliferation, invasion, and metastasis. The rising global incidence and mortality rates impose a substantial burden on healthcare systems, thereby constituting a critical worldwide public health challenge ( 1 ). Fundamentally, tumorigenesis arises from the accumulation of genetic alterations, with studies indicating that 2 to 8 driver gene mutations are harbored by most human cancers ( 2 ). Conventional therapeutic modalities, including surgery, chemotherapy, radiotherapy, and their combinations, remain the standard of care. Tumors are physically removed via surgery, whereas cancer cells are eliminated by radiotherapy and chemotherapy through interference with their growth, proliferation, and survival. However, such interventions are frequently evaded by tumors through multiple mechanisms, such as acquired mutations and cancer stem cell-mediated drug resistance, ultimately resulting in recurrence, metastasis, and therapeutic failure ( 3 ). Furthermore, conventional therapies are frequently accompanied by severe adverse effects; anorexia, muscle atrophy, or central nervous system complications (such as seizures, headaches, cerebrovascular complications, vision loss, and myelopathy) may be caused by chemotherapy ( 4 , 5 ). Immunotherapy has been established as a pivotal component of modern oncology due to the urgent need for durable, low-toxicity therapeutic options. Remarkable clinical breakthroughs have been achieved by cancer immunotherapy, which employs strategies to mobilize the host immune system and activate endogenous immune cells to eliminate malignancies ( 6 – 8 ). The “cancer immunity cycle” typically comprises six critical steps: (1) tumor-antigen uptake and processing by antigen-presenting cells; (2) migration of antigen-presenting cells to lymphoid organs; (3) tumor-antigen presentation fine-tuned by co-stimulatory and co-inhibitory signals, leading to the activation of tumor-specific T cells and their differentiation into effector T cells within lymphoid organs; (4) egress of tumor-specific effector T cells from lymphoid organs into the peripheral blood and their trafficking to tumor sites; (5) tumor antigen recognition and tumor cell lysis; and (6) contraction of effector T cells along with the generation of tumor-specific memory T cells ( 9 ). A self-propagating cycle essential for eliciting effective antitumor immunity is established by these steps. However, immune escape is orchestrated by tumors primarily through the fostering of an immunosuppressive microenvironment, suppression of immune effector function, restriction of immune-cell infiltration, and the reduction of antigen recognition ( 10 – 13 ). To restore the cancer immunity cycle and reactivate antitumor responses, these escape mechanisms are generally targeted by current immunotherapeutic strategies ( 14 ). These strategies are broadly classified into five categories: (1) Tumor vaccines: tumor antigens are introduced into patients to enhance tumor immunogenicity, activate the host’s immune system, and induce immune responses, thereby controlling or eliminating tumors ( 15 , 16 ); (2) Cytokine immunotherapy: cytokines are modulated to promote the maturation of immune cells (such as macrophages, natural killer cells, T lymphocytes, and dendritic cells), thereby enhancing their capacity to eliminate tumors ( 17 – 19 ); (3) Immune checkpoint blockade therapy: the immunosuppression of cytotoxic T lymphocytes by immune checkpoints is relieved, thereby restoring their ability to kill tumor cells ( 13 , 20 ); (4) Cellular immunotherapy: patients are infused with immune cells that have been activated and engineered ex vivo, enabling them to exert potent antitumor effects in vivo , which has demonstrated promising clinical outcomes ( 21 , 22 ); and (5) Small-molecule immunotherapy: small-molecule compounds are employed to modulate the activity of key enzymes or relevant receptors in immune pathways, an approach designed to improve the immune microenvironment, overcome immunosuppression, and activate antitumor immune responses ( 23 , 24 ). Despite the clinical approval and efficacy of various immunotherapies, their broader application remains hindered by significant barriers. Clinical data indicate that limited response rates to immunotherapy are observed in most solid tumors, typically ranging from 20% to 30% ( 25 ). Furthermore, immune-related adverse events are experienced by up to 37.7% of patients, which often necessitates the discontinuation of treatment due to severe side effects ( 26 ). To address these limitations, advanced nanoparticles have been engineered to selectively deliver therapeutic agents to tumor sites, thereby facilitating targeted cancer immunotherapy ( 27 – 29 ). Nanodrug delivery systems have been increasingly explored in cancer immunotherapy to improve tumor-directed delivery, promote immunogenic cell death, remodel the immunosuppressive TME, and interfere with tumor immune-evasion pathways ( 30 ). It was demonstrated in a meta-analysis by Wilhelm et al. that nanoparticle delivery efficiency remains remarkably low, with a median of only 0.7% of the administered dose ultimately reaching solid tumors. Manufacturing scalability and cost-effectiveness are significantly hampered by this inefficiency, while potential toxicity is exacerbated and therapeutic efficacy is limited ( 31 ). Although the development of numerous advanced nanoparticles has been prompted by this inefficiency, no significant improvement in the average delivery efficiency has been observed in recent years. Clinical translation is further impeded by the complex, heterogeneous physicochemical nature of the immunosuppressive tumor microenvironment (TME) and the physiological discrepancies between animal models and humans ( 32 , 33 ). Recently, tumor-activated prodrug nanoparticles (PDNPs) have emerged as a promising strategy for targeted cancer immunotherapy. Prodrugs represent pharmacologically inactive derivatives that undergo chemical transformation, wherein active parent drugs are released upon triggering by TME biomarkers (including enzymes, acidity, redox potential and hypoxia) or exogenous stimuli (such as ultrasound and light). The non-targeted toxicity associated with the therapeutic agents themselves is significantly mitigated by this mechanism ( 34 ). A representative strategy for constructing PDNPs involves the self-assembly of prodrug molecules through intermolecular covalent or noncovalent interactions, including hydrophobic effects, electrostatic interactions, and hydrogen bonding ( 35 – 37 ). Such self-assembled PDNPs can combine tumor-responsive drug activation with a reduced dependence on auxiliary carrier materials, thereby minimizing premature drug leakage and potentially decreasing carrier-associated burden ( 38 ). Furthermore, chemotherapeutics, photothermal agents, or sonosensitizers can be co-assembled with PDNPs, facilitating the integration of immunotherapy with multimodal treatments to overcome monotherapy resistance ( 39 – 42 ). In this review, strategies for achieving precise tumor targeting with PDNPs are systematically summarized, with a focus on their mechanisms in synergistic immunotherapy and potential for clinical translation, thereby providing a reference framework for the future design of PDNPs. The major activation mechanisms and design strategies of tumor-activated PDNPs are summarized in Figure 1 . Figure 1 Stimuli-responsive mechanisms of PDNPs for cancer immunotherapy. 2 Tumor microenvironment-activated PDNPs The tumor microenvironment is a complex ecosystem comprising a diverse array of immune cells, cancer-associated fibroblasts, endothelial cells, pericytes, and other tissue-specific cell types, such as adipocytes and neurons ( 43 ). Hypoxia is a hallmark of solid tumors, primarily resulting from aberrant tumor vasculature and elevated metabolic oxygen consumption during rapid cell proliferation ( 44 , 45 ). Hypoxia-inducible factors, the best-characterized transcription factors in tumor hypoxia, regulate the transcription of numerous genes involved in every step of metastatic progression ( 46 ). Beyond hypoxia, aerobic glycolysis (the Warburg effect) constitutes another distinct metabolic feature, where the majority of glucose is converted to lactate even in the presence of oxygen. This metabolic reprogramming results in an acidic extracellular pH (6.5–6.9) ( 47 , 48 ). As a critical intracellular antioxidant, glutathione (GSH) maintains intracellular redox homeostasis and participates in antioxidant defense. However, its elevated levels in tumor cells can significantly compromise therapeutic efficacy ( 49 , 50 ). Certain overexpressed enzymes in the TME, such as matrix metalloproteinases and NAD(P)H:NQO1, play crucial roles in tumor invasion, migration, and proliferation ( 51 ). These unique physicochemical properties of the TME can be exploited by nanocarriers to achieve site-specific, controlled prodrug activation within tumor tissues ( 52 ). In this section, we categorize tumor-responsive PDNPs by their activation mechanisms and highlight how these designs elicit antitumor immune responses ( Table 1 ). Table 1 Type Tumor-sensitive group ICD inducer/immune activation strategy Combination drug/modality Cell lines/animal models Therapeutic efficacy Source pH Piperidine groups GOD PTX Anti-PD-1 Panc02; orthotopic Panc02-Luc/C57BL/6J Median survival 80 d ( 34 ) PEMA DOX NLG-919 4T1; bilateral 4T1/BALB/c Distant tumor: complete inhibition ( 54 ) Hydrazone bond EPI Anti-PD-1 4T1, MDA-MB-231; 4T1/BALB/c TIR ~79% ( 56 ) Benzoic imine bond Hydrazone bond DOX Anti-PD-1 CT26, 4T1; CT26/4T1-bearing mice Tumor suppression ~74%/85% ( 58 ) Schiff base bond DOX – H22, M2 macrophages, HUVEC; H22-bearing mice TIR 81% ( 59 ) Hydrogen bonds – Anti-PD-L1 MC38; MC38/C57BL/6 Survival 40% ( 60 ) ROS Thioether bond DOX DHA – 4T1; 4T1-bearing mice TIR ~80% ( 39 ) PPE R848 Anti-PD-1 MB49, RAW264.7; MB49-bearing mice; patient organoids TIR 98% ( 61 ) Phenylboronic ester CPT DMXAA B16-F10, 4T1; B16-F10/C57BL/6; orthotopic 4T1/BALB/c Tumor burden ~1/6 of PBS ( 62 ) Thioketal bond SN38 Anti-PD-L1 CT26, HCoEpiC; subcutaneous/orthotopic CT26/BALB/c CR 2/5 ( 63 ) GSH Disulfide bond PTX 1MT 4T1, L929, DC2.4; 4T1/BALB/c Apoptosis 74.3% ( 65 ) Disulfide bond Curcumin monomers T780 PTT PDT AMC-HN-8, SCC7; AMC-HN-8/BALB/c nude Tumor regression; recurrence reduced ( 66 ) Enzyme RRK peptide Verteporfin PROTAC GL261; subcutaneous/orthotopic GL261/C57BL/6 CR 100% ( 37 ) Peptide Semiconducting polymer Ultrasound irradiation 4T1; bilateral 4T1/BALB/c Primary/distant TIR 89%/90% ( 68 ) FRRL peptide DOX Anti-PD-L1 antibody CT26, H9C2; CT26-bearing mice CR 100% ( 35 ) DHPVGLLARD Peptide R848 Cisplatin (Pt) B16F10, RAW264.7; B16F10/C57BL/6 Survival 67% ( 69 ) GALGLPG peptide Pheophorbide a NLG-919 PDT CT26; CT26/BALB/c (primary/abscopal) Survival >80% ( 70 ) Ester bond Stapled KLA peptide Anti-PD-L1 4T1; bilateral 4T1/BALB/c Primary/distant TIR 88.0%/97.3% ( 36 ) β-glucuronidase IMDQ – RAW Blue reporter cells; IFNβ-reporter mice/draining LNs IFN-β >3-fold increase ( 72 ) Hypoxia Nitroaromatic linker PTX JQ1 4T1; 4T1-bearing mice DC maturation +36.9% ( 78 ) Nitroaromatic group CPT – 4T1, RAW264.7; orthotopic 4T1/BALB/c Highest survival ( 79 ) 4-nitrobenzyloxy group Cu(DTC) 2 Curcumin – 4T1; 4T1-bearing mice 4T1 viability 10.3% ( 80 ) Ester bond – CA4‐NPs CT26; CT26-bearing mice TIR 98.1% ( 81 ) Azo linker DTC-Cu – 4T1; 4T1/BALB/c TIR 79.23% ( 42 ) Azo linker IMDQ iRFA H22, DC2.4; subcutaneous/bilateral/orthotopic H22/BALB/c Tumor suppression 96.6% ( 82 ) Azo linker AQ4N HIFU 4T1; bilateral 4T1/BALB/c Survival 90% ( 83 ) Azide group IMDQ CA4 4T1, MC38, CT26; corresponding mouse models Tumor eradication without recurrence ( 84 ) Azide group R848 Anti-PD-1 4T1, CT26, MC38; BALB/c/C57BL/6 mice TSR 99.4% (4T1); 4/5 cured (CT26) ( 85 ) Summary of TME-responsive PDNPs for targeted cancer immunotherapy. TME, tumor microenvironment; PDNPs, prodrug nanoparticles; ICD, immunogenic cell death; ROS, reactive oxygen species; GSH, glutathione; GOD, glucose oxidase; PTX, paclitaxel; PD-1, programmed cell death protein 1; BA, betulinic acid; Ce6, chlorin e6; PD-L1, programmed death-ligand 1; PDT, photodynamic therapy; PEMA, 2-(pentamethylene imino)ethyl methacrylate; DOX, doxorubicin; NLG-919, 1-cyclohexyl-2-(5H-imidazo[5,1-a]isoindol-5-yl)ethanol; OXP, oxaliplatin; CD47, cluster of differentiation 47; EPI, epirubicin; DHA, dihydroartemisinin; PPE, phenylboronic acid pinacol ester; R848, resiquimod; CPT, camptothecin; DMXAA, 5,6-dimethylxanthenone-4-acetic acid; SN38, 7-ethyl-10-hydroxycamptothecin; 1MT, 1-methyl-tryptophan; T780, TPGS-modified IR780 photothermal agent; PTT, photothermal therapy; PROTAC, proteolysis-targeting chimera; Pt, platinum; NPs, nanoparticles; MSA-2, non-nucleotide stimulator of interferon genes agonist; KLA, pro-apoptotic KLA peptide; IMDQ, imidazoquinoline; JQ1, bromodomain and extraterminal domain inhibitor JQ1; DTC, diethyldithiocarbamate; CA4, combretastatin A4; iRFA, incomplete radiofrequency ablation; AQ4N, banoxantrone; HIFU, high-intensity focused ultrasound; Azo, azobenzene. Abbreviations: TIR, tumor inhibition rate; CR, complete regression. 2.1 pH-responsive PDNPs pH-responsive PDNPs are typically engineered by incorporating pH-sensitive moieties, such as amines or carboxyl groups, into the prodrug architecture ( 34 ). Protonation of these moieties within the acidic TME triggers nanostructure disassembly, thereby enabling tumor-specific drug release. A pH-responsive micellar nanoreactor, pro-PTX NRs, was developed by incorporating piperidine units (pKa ≈ 6.75). This design enables the nanoreactor to respond to the weakly acidic TME (pH ≈ 6.5), where protonation of the piperidine groups induces nanostructural swelling. This swelling restores the encapsulated glucose oxidase ( Figure 2 ), which catalyzes glucose oxidation to generate hydrogen peroxide (H 2 O 2 ), subsequently cleaving the oxalate ester linkages to release active paclitaxel. Approximately 60% of the prodrug was activated within 48 hours in vitro . In an orthotopic pancreatic cancer model, combining pro-PTX NRs with a PD-1 inhibitor significantly suppressed tumor growth and extended the median survival of mice from 31 days (control group) to 80 days. The nano-system COS-BA/Ce6 NPs, co-assembled from a chitosan oligosaccharide-modified betulinic acid prodrug and the photosensitizer Chlorin e6 (Ce6), employs synergistic chemo-photodynamic therapy to induce immunogenic cell death (ICD) ( 53 ). This system responds to the weakly acidic TME through protonation of the amino groups on chitosan oligosaccharide, which disrupts the hydrogen-bonding network within the nanoparticles and triggers responsive disassembly, thereby releasing the chemotherapeutic component betulinic acid and the photosensitizer Ce6. In a 4T1 breast cancer model, combined with anti-PD-L1 immunotherapy, this system achieved an inhibition rate of 80.3% against the primary tumor and successfully activated a systemic anti-tumor immune response, suppressing the growth of distant non-irradiated tumors. Figure 2 (A) Activated GOD catalyzes glucose oxidation to generate ROS, triggering prodrug cleavage and release of active paclitaxel. The cascade induces cytotoxicity and immunogenic cell death, enabling synergistic oxidation–chemo–immunotherapy ( 34 ). This image is available under the CC BY 4.0 license. (B) Schematic illustration of cancer-accessing TA-OBL to boost antitumor immune responses and synergize ICBs-mediated immunotherapy. TA-OBL would be activated by highly expressed legumain in tumor to promote their intratumoral permeation and accessibility to cancer cell fractions. Afterward, TA-OBL undergoes size-enlargement in intracellular acidic environments to prolong their tumor retention ( 55 ). Copyright 2020, Wiley. (C) Chemical structure and fabrication of PDNPs and the mechanism of pH cascade-responsive conversion and drug release ( 58 ). Copyright 2022, Wiley. (D) Schematic illustration of synthesis and self-assembly of mAb-CD163 + -PDNPs nanoparticles modified by CD163 + monoclonal antibody, which can target and deplete tumor-associated macrophages ( 59 ). This image is available under the CC BY 4.0 license. Beyond merely leveraging protonation in the acidic milieu to trigger the disassembly of PDNPs, more advanced nanoscale prodrug systems also enable precise regulation of PDNPs size, thereby prolonging their retention time within tumor tissues. Japir et al. constructed a β‐gal@PSLC system, in which the protonation of PEMA units (
## Related Clinical Research

- [Gene-based immunotherapy in osteosarcoma: full article text not available on source page](https://medichelpline.com/clinical-feed/frontiers-in-immunology-16-gene-based-immunotherapy-in-osteosarcoma-from-oncolytic-vectors-to-engineered.md)
- [Icaritin Combined with TACE for Hepatocellular Carcinoma: Analysis by Child‑Pugh Class](https://medichelpline.com/clinical-feed/frontiers-in-immunology-12-efficacy-analysis-of-icaritin-combined-with-transarterial-chemoembolization-in.md)
- [SRSF1 controls transcription and alternative splicing to alter p53 signaling and genome maintenance](https://medichelpline.com/clinical-feed/biorxiv-4-srsf1-coordinates-transcription-and-alternative-splicing-to-modulate-p53-and.md)
- [pH-Responsive Chitosan–Boswellic Acid Nanogels for Sustained Sunitinib Delivery and Lung Tumor Sup](https://medichelpline.com/clinical-feed/pubmed-42713680.md) (DOI: 10.1021/acsami.6c02925)
- [Response-Adapted Bladder Preservation in MIBC: RETAIN-2 Phase II Results and ctDNA Dynamics](https://medichelpline.com/clinical-feed/medrxiv-2-response-adapted-bladder-preservation-in-muscle-invasive-bladder-cancer-results.md)

## Navigation
- [← Back to Infectious Disease Feed](https://medichelpline.com/clinical-feed/infectious-disease.md)
- [← All Clinical Specialties](https://medichelpline.com/clinical-feed.md)
## Medical & Regulatory Disclaimer

> [!CAUTION]
> MedicHelpline content is structured for research, educational, and professional discovery purposes. It does not constitute individual medical advice, clinical diagnosis, or treatment recommendations.
> Always verify dosing, contraindications, and regulatory alerts against official product labeling and primary regulatory sources before clinical decision-making.