---
title: "Gene-based immunotherapy in osteosarcoma: full article text not available on source page"
id: "frontiers-in-immunology-16-gene-based-immunotherapy-in-osteosarcoma-from-oncolytic-vectors-to-engineered"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-16-gene-based-immunotherapy-in-osteosarcoma-from-oncolytic-vectors-to-engineered"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1920347"
published_at: "2026-08-04T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Gene-based immunotherapy in osteosarcoma: full article text not available on source page
## Provenance & Clinical Metadata
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- **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.2026.1920347)
- **Published At:** 2026-08-04T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
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## Clinical Analysis & Structured Key Points
Frontiers | Gene-based immunotherapy in osteosarcoma: from oncolytic vectors to engineered immune cells MINI REVIEW article Front. Immunol. , 04 August 2026 Sec. Cancer Immunity and Immunotherapy Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1920347 Published in Frontiers in Immunology Cancer Immunity and Immunotherapy 7 impact factor 11.3 citescore Part of a Research Topic Gene Therapy Strategies for Immunotherapy Submission open 11k views 7 articles Editor & Reviewers Edited by R L ROBIN LEWIS JONES Reviewed by S S Sumit Sheoran L G Luca Giacchi Outline Figures and Tables Figure 1 View in article Figure 2 View in article Table 1 Comparison of major oncolytic viral platforms explored for osteosarcoma and related pediatric solid tumors. View in article Table 2 Comparison of viral versus non-viral gene delivery systems for osteosarcoma immunotherapy [sources ( 10 , 11 , 42 – 49 )]. View in article Table 3 Representative gene-based immunotherapy strategies for osteosarcoma and their translational maturity. View in article MINI REVIEW article Front. Immunol. , 04 August 2026 Sec. Cancer Immunity and Immunotherapy Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1920347 Gene-based immunotherapy in osteosarcoma: from oncolytic vectors to engineered immune cells J J Junliang Jia W X Wei Xie J Z Jiawang Zhou W W Weidong Wu S Z Shuliang Zhou * Department of Orthopedics, Suzhou Ninth People’s Hospital, Soochow University, Suzhou, Jiangsu, China Article metrics View details Abstract Osteosarcoma remains difficult to cure once it metastasizes, recurs, or becomes resistant to chemotherapy. Surgery combined with multi-drug chemotherapy improves outcomes in localized disease, but outcomes for high-risk patients have plateaued, prompting renewed interest in immunotherapy. However, immune checkpoint blockade has limited efficacy in unselected osteosarcoma patients: in SARC028, one objective response was observed among 22 patients with osteosarcoma treated with pembrolizumab. This limited response is consistent with antigen heterogeneity, enrichment of immunosuppressive myeloid populations, insufficient cytotoxic lymphocyte infiltration, matrix-associated immune exclusion, and metastatic immune adaptation. Gene-based immunotherapy offers a complementary strategy. When endogenous immune priming is inadequate, these platforms may initiate, reshape, or amplify antitumor immunity by promoting oncolytic antigen release, local cytokine or chemokine expression, engineered immune-cell recognition, or non-viral delivery of immunomodulatory payloads. This article discusses oncolytic vectors, cytokine-armed vectors, CAR-T and CAR-NK cells, TCR- or neoantigen-directed strategies, and non-viral gene delivery systems as potential approaches for reshaping osteosarcoma immunity. It also examines combination strategies and translational challenges in pediatric and adolescent patients. Beyond summarizing platform-level evidence, we distinguish findings generated directly in osteosarcoma from evidence extrapolated from other tumor types, identify the principal unresolved knowledge gaps for each platform, and summarize the current osteosarcoma-specific clinical trial landscape to clarify the translational maturity of these strategies. 1 Introduction Osteosarcoma is the most common primary malignant bone tumor in children and adolescents, yet advances in tumor biology have translated into only limited therapeutic benefit. Surgery combined with multi-drug chemotherapy can cure some patients with localized disease, but the prognosis remains poor for patients with lung metastases, recurrence, unresectable lesions, or chemotherapy resistance ( 1 ). Standard multi-agent chemotherapy regimens (typically methotrexate, doxorubicin, and cisplatin) have not changed substantially in more than three decades, carry considerable acute and long-term toxicity in a predominantly pediatric and adolescent population, and add little further benefit once micrometastatic disease becomes overtly resistant; this therapeutic stagnation is the practical justification for pursuing gene-based immunotherapy as a mechanistically distinct approach. Contemporary reviews still describe osteosarcoma as a disease with a treatment plateau, and intensive cytotoxic therapy rarely addresses the core issues of drug-resistant or disseminated osteosarcoma ( 2 , 3 ). This clinical bottleneck has driven interest in immunotherapy, although clinical activity has so far been limited. In SARC028, 40 patients with bone sarcoma were evaluable for response: two (5%) had an objective response, consisting of one response among 22 patients with osteosarcoma and one among five with chondrosarcoma; no objective response was reported in the 13-patient Ewing sarcoma subgroup ( 4 ). Thus, osteosarcoma-specific activity was limited to one response among 22 patients, an insufficient signal to support unselected checkpoint blockade. This does not mean that osteosarcoma is immunologically irrelevant, but rather suggests that the disease often lacks the immune conditions required for standard checkpoint therapy to be effective: insufficient pre-activated effector T cells, excessive myeloid suppression, and poorly coordinated antitumor immune responses. In this context, gene-based immunotherapy is best understood as a strategy for immune-niche reprogramming. The platforms reviewed here are considered according to the osteosarcoma barrier they are designed to address: oncolytic vectors can overcome weak antigen release and innate sensing; cytokine- or chemokine-armed vectors can strengthen local priming and effector-cell recruitment; engineered immune cells can enforce antigen recognition but must overcome trafficking, persistence, exhaustion, and antigen escape; and non-viral systems can deliver transient payloads to tumor, immune, stromal, or metastatic compartments. Because much of the mechanistic rationale for these platforms was first established in melanoma, glioma, or adult carcinomas, this review explicitly distinguishes evidence generated directly in osteosarcoma from evidence extrapolated from other tumor types, while highlighting the principal unresolved questions that should guide future osteosarcoma-focused studies throughout the review. This Mini Review draws on English-language primary clinical studies, osteosarcoma-specific preclinical studies, and comparative canine osteosarcoma models, with recent reviews used mainly to identify platform classes and unresolved translational questions. Evidence from broader sarcoma or solid-tumor studies is included selectively when osteosarcoma-specific data are unavailable and is identified as extrapolative rather than presented as disease-specific proof. Literature published through July 2026 was considered. 2 Immune resistance in osteosarcoma and the rationale for gene-based therapy The rationale for gene-based immunotherapy is grounded in the immunophenotype of osteosarcoma itself. Unlike much of the vector- and cell-engineering literature discussed in later sections, the evidence summarized in this section is drawn directly from human or canine osteosarcoma specimens rather than extrapolated from other tumor types, and therefore provides the most disease-specific rationale available. Zhou et al. constructed a single-cell RNA atlas of advanced osteosarcoma, revealing significant intratumoral heterogeneity, variable antigen presentation, and immunosuppressive cellular programs dominated by tumor-associated macrophages and osteoclasts ( 5 ). Jiang et al. further identified prognostically distinct osteosarcoma subtypes through multi-omics analysis, supporting the view that osteosarcoma is not always an immune-cold tumor, but often presents an immune-excluded phenotype, in which immune cells are present within the tumor but functionally segregated from malignant cells rather than truly absent ( 6 ). Some lesions contain immune cells, but these cells may be spatially separated from viable tumor regions, dominated by a suppressive myeloid state, or insufficient to form a durable cytotoxic response. Myeloid biology is particularly important. Tumor-associated macrophages, monocyte-derived populations, and myeloid-derived suppressor cells can limit T-cell priming and effector function. As Deng et al. showed through pre- and post-chemotherapy atlas analysis, neoadjuvant chemotherapy can reshape this immune landscape ( 7 ), but cannot reliably transform every lesion into an inflammatory, checkpoint-treatment-sensitive tumor. He et al. further confirmed at single-cell resolution that neoadjuvant chemotherapy alters but does not eliminate the immunosuppressive microenvironment ( 8 ). A comparative canine study by Regan et al. showed that losartan combined with the kinase inhibitor toceranib produced significant clinical benefit in dogs with metastatic osteosarcoma by blocking monocyte recruitment, providing translational evidence for targeting the myeloid circuit ( 9 ). Conventional immunotherapy is also limited by other barriers. Osteosarcoma-associated antigens are heterogeneous and may be poorly expressed. Cytotoxic T cells may have difficulty trafficking into dense osteoid or mineralized tumor regions. NK cell activity can be limited by inhibitory cytokines and abnormal angiogenesis. Lung metastases can establish an immune microenvironment distinct from that of the primary bone lesion. Consequently, PD-1 blockade alone may lack a sufficiently active pre-existing immune response to amplify. Gene-based strategies may instead establish the immunological conditions required for treatment response: oncolytic vectors can promote tumor-antigen release and induce innate immune sensing; armed vectors can deliver payloads that are too toxic or too short-lived for systemic administration; and engineered cells can redirect recognition to specific targets. The key issue is not whether gene therapy can kill osteosarcoma cells in isolation, but whether it can transform resistant lesions into immune-responsive niches ( Figure 1 ). A key knowledge gap is that no prospectively validated non-invasive marker currently distinguishes among immune-excluded, immune-desert, and transiently inflamed osteosarcoma lesions, and without a biopsy this state cannot be determined in practice, which limits rational, upfront selection of gene-based immunotherapy platforms. Figure 1 Gene-based immunotherapy reprograms the osteosarcoma microenvironment from an immune-resistant to an immune-responsive state. Before intervention, the primary bone lesion is characterized by an osteoid/mineralized matrix barrier, abnormal vasculature, weak antigen presentation, limited CD8 + T-cell trafficking, and immunosuppressive myeloid populations, including tumor-associated macrophages and myeloid-derived suppressor cells. The lung metastatic niche represents a distinct microenvironment with systemic delivery requirements and variable myeloid suppression. Gene-based approaches—including oncolytic viruses, cytokine-armed vectors, CAR-T/CAR-NK cells, and non-viral delivery systems—may promote tumor-antigen release, dendritic-cell priming, cGAS–STING-associated innate sensing, chemokine-guided immune-cell trafficking, and cytotoxic lymphocyte activity. The schematic illustrates proposed mechanisms of immune reprogramming and does not imply that all pathways have been clinically validated in osteosarcoma. Warm red and brown tones denote immune-resistant components and suppressive signals, whereas blue and green tones denote immune-responsive components and therapeutic immune activation. CAR, chimeric antigen receptor; cGAS, cyclic GMP–AMP synthase; DAMP, damage-associated molecular pattern; IFN, interferon; LNP, lipid nanoparticle; MDSC, myeloid-derived suppressor cell; ROS, reactive oxygen species; STING, stimulator of interferon genes; TAM, tumor-associated macrophage. 3 Oncolytic vectors as in situ immune activators Oncolytic vectors have a dual role, which is particularly relevant to osteosarcoma. They can directly lyse tumor cells, but their broader value may lie in transforming tumor tissue into sites of in situ immune activation. The oncolytic process releases tumor antigens, damage-associated molecular patterns, viral pathogen-associated signals, and inflammatory cytokines. These events can promote dendritic-cell activation, type I interferon signaling, cross-presentation, and the activation of T and NK cells ( 10 , 11 ). For immune-resistant tumors, this vaccine-like function may be more important than the proportion of cells infected at a given time point. Osteosarcoma-specific evidence remains limited but is biologically informative; osteosarcoma-related reviews also summarize major vector classes and delivery barriers ( 12 , 13 ). Martinez-Velez et al. demonstrated significant antitumor activity of the oncolytic adenovirus VCN-01, which encodes hyaluronidase to degrade the extracellular matrix and improve viral spread, in a pediatric osteosarcoma model by overcoming the matrix barrier that limits conventional viral penetration ( 14 ). The same team subsequently showed that 4-1BBL-armed oncolytic adenovirus produced antitumor effects and durable immune memory in a pediatric osteosarcoma model, suggesting that the importance of payload design extends beyond the oncolytic scaffold itself ( 15 ). Makielski et al. reported that neoadjuvant systemic vesicular stomatitis virus was safe in dogs with naturally occurring osteosarcoma and may enhance long-term survival, providing a comparative model for systemic oncolytic delivery that more closely reflects the biology of human osteosarcoma than conventional rodent models ( 16 ). An in vitro osteosarcoma study of an anti-PD-1 sdAb-armed oncolytic virus demonstrated that vectors can be designed to carry locally delivered checkpoint blockade ( 17 ). Clinically, however, osteosarcoma-specific evidence for oncolytic virotherapy remains limited to early-phase feasibility studies: a phase I trial of intratumoral HSV1716 in children with relapsed extracranial solid tumors, including osteosarcoma, demonstrated safety and evidence of viral replication but no objective tumor responses ( 18 ), and a Children’s Oncology Group phase I trial of intravenous reovirus in pediatric sarcomas showed a similar pattern of acceptable safety without objective tumor regression ( 19 ); no osteosarcoma-restricted oncolytic-virus trial has yet produced randomized or biomarker-stratified efficacy data or reported an osteosarcoma-specific efficacy endpoint. Table 1 compares the major oncolytic viral platforms explored for osteosarcoma and related pediatric solid tumors in terms of their advantages and limitations. Table 1 Platform Genome/cargo capacity Delivery route Key advantages Key limitations Osteosarcoma-specific evidence/stage Adenovirus (e.g., VCN-01, 4-1BBL-armed) dsDNA; ~7–8 kb; non-integrating Intratumoral; intravenous delivery evaluated preclinically Large transgene capacity; can be armed with matrix-degrading enzymes (hyaluronidase) to overcome the osteoid barrier; well-characterized platform biology and engineering Pre-existing neutralizing immunity common; mainly local rather than systemic reach Pediatric osteosarcoma xenograft models ( 14 , 15 ); preclinical Herpes simplex virus (HSV-1, e.g., HSV1716) dsDNA; very large capacity; engineered lytic/oncolytic platform Intratumoral injection Large payload capacity; extensive pediatric intratumoral safety experience; strong local immune activation Mainly local administration; limited penetration of dense matrix; theoretical latency/reactivation risk Phase I pediatric trial including osteosarcoma: safe, no objective responses ( 18 ); clinical (phase I) Vaccinia virus dsDNA; >25 kb capacity Intratumoral or intravenous (relatively complement-resistant) Systemic delivery feasible; rapid replication; strong innate activation; cytokine arming with IL-12 showed an improved preclinical safety profile ( 20 ) Prior vaccination history affects immunity; systemic cytokine toxicity risk when armed; shedding risk Tested in osteosarcoma-specific preclinical models, including SIRPα-Fc-armed vaccinia virus in an immunocompetent murine model ( 21 ); no osteosarcoma-specific clinical evidence; preclinical Vesicular stomatitis virus (VSV) Negative-sense RNA; moderate capacity; rapid replication Systemic (intravenous) feasible Fast onset; low human seroprevalence; systemic delivery well tolerated in large-animal studies Neurotoxicity risk with wild-type strains (mitigated by IFN-sensitizing engineering); less clinical experience overall Safe, associated with improved survival in canine osteosarcoma ( 16 ); preclinical (large-animal) Comparison of major oncolytic viral platforms explored for osteosarcoma and related pediatric solid tumors. dsDNA, double-stranded DNA; HSV, herpes simplex virus; IFN, interferon; VSV, vesicular stomatitis virus. Armed vectors extend this concept. IL-12-armed vaccinia virus demonstrates that cytokine payloads can be localized to enhance immune activation while attempting to reduce systemic toxicity ( 20 ). Osteosarcoma-specific preclinical evidence also includes SIRPα-Fc-armed vaccinia virus, which delayed tumor progression and improved survival in an immunocompetent murine model ( 21 ). The GM-CSF-expressing talimogene laherparepvec demonstrated that local oncolytic immunotherapy can be clinically active, although evidence from melanoma cannot be directly extrapolated to osteosarcoma ( 22 ). Cytokine-armed herpes simplex virus vectors further support localized immune activation, although this evidence remains largely extrapolative for osteosarcoma ( 23 ). For osteosarcoma, payload selection should be matched to the dominant immune deficit: chemokines may be useful when effector cells cannot enter the tumor, whereas IL-12 or co-stimulatory ligands may be more relevant when dendritic-cell priming and activation are weak. The most logical role of oncolytic vectors in osteosarcoma is not as stand-alone lytic agents, but as programmable local immune activators that can provide a biological rationale for subsequent checkpoint blockade or cell therapy. A key knowledge gap is that with the exception of small, single-arm pediatric safety trials, no oncolytic vector has been tested against a defined osteosarcoma biomarker hypothesis (for example, baseline myeloid infiltration or antiviral immune status), so it remains unknown which patients are most likely to benefit. 4 Engineered immune cells for osteosarcoma Engineered immune cells address a different limitation: endogenous lymphocytes may not be able to recognize osteosarcoma strongly enough or persist in the suppressive niche. CAR-T cells are the most mature platform. Ahmed et al. reported the first clinical trial of HER2-specific CAR-T cells for HER2-positive sarcoma, treating 19 patients, including osteosarcoma cases, with dose escalation to 1 × 10^8 cells/m². Treatment was feasible and well tolerated, with no dose-limiting toxicities; 4 of the 17 evaluable patients achieved disease stabilization for 12 weeks to 14 months, but no objective response was observed under RECIST criteria ( 24 ). Earlier work by the same team showed that genetic modification of T cells can overcome the low antigen density in osteosarcoma, which is an important proof of concept for tumors with weak target expression ( 25 ). Target selection is also evolving. IL11Rα-guided T cells induced regression of established osteosarcoma lung metastases in preclinical models ( 26 ). NKG2D-CAR memory T cells may partly mitigate dependence on a single conventional tumor antigen by recognizing stress-induced ligands expressed by osteosarcoma cells ( 27 ). GD2-guided CAR-T cells with low-dose doxorubicin have shown preclinical synergy, suggesting that appropriately dosed chemotherapy may sensitize tumor cells to engineered immunotherapy without simply increasing toxicity ( 28 ). B7-H3 has attracted particul
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