A review led by Professor Yanhong Shi and Dr. Jia Li at the City of Hope National Medical Center was published on September 15, 2026, in Volume 2 of the journal Immunity & Inflammation . The article systematically summarizes the biological rationale, engineering strategies, clinical translation challenges, and future directions for combining oncolytic viruses (OVs) with CAR-T and CAR-NK cells. The authors propose that OVs and CAR cells are not merely additive therapies but can be co-designed into a multi-module immunotherapeutic system that operates continuously within the tumor.
CAR cell therapy has revolutionized the treatment of certain hematological malignancies. However, when CAR-T and CAR-NK cells enter solid tumors, their efficacy remains limited by multiple factors: high antigen heterogeneity, poor effector cell infiltration, sustained immunosuppression within the microenvironment, and difficulty maintaining CAR cell persistence and function. How can CAR cells be enabled to “see” more tumor targets, infiltrate more regions, and sustain their activity? Oncolytic viruses may provide an important part of the answer.
Solid tumors present a complex barrier system encompassing targeting, access, efficacy, and safety. Target antigens often display marked spatial and temporal heterogeneity. When CAR cells exert continuous selective pressure, low-antigen or antigen-negative subpopulations may gradually become enriched, leading to antigen escape. Meanwhile, abnormal vasculature, dense extracellular matrix, and complex tissue architecture impede CAR cell infiltration. Even upon entry, hypoxia, nutrient deprivation, immunosuppressive cytokines, TGF-β, immune checkpoints, and tumor-associated myeloid cells can drive CAR cell functional exhaustion. These challenges are particularly pronounced in glioblastoma (GBM).
The review emphasizes that the value of OVs extends beyond direct tumor cell lysis. When OVs infect and lyse tumor cells, they release tumor-associated antigens, pathogen-associated molecular patterns, and damage-associated molecular patterns. These signals activate antigen-presenting cells, induce inflammatory cytokines and chemokines, and promote the recruitment of dendritic cells, macrophages, NK cells, and endogenous T cells, converting a “cold” tumor microenvironment into a more immunologically active site. The authors propose a self-amplifying circuit between OVs and CAR cells: “ OV infection leads to tumor lysis and release of antigens and danger signals, which drive immune activation and CAR cell recruitment and infiltration, followed by CAR-mediated killing and further antigen release, creating a positive feedback loop. ” This self-amplifying circuit distinguishes OV–CAR combination from simple additive drug combinations.
A key engineering strategy addresses the problem of missing or heterogeneous CAR targets. OVs can be engineered to deliver payloads that force infected tumor cells to express new surface antigens, such as truncated CD19. This approach temporarily converts CD19-negative solid tumor cells into “CD19-positive” targets recognizable by CAR-T cells. The strategy separates two problems: The OV determines “where to install the target,” while the CAR determines “how to kill the marked cell.”
Building on this concept, the team constructed an OVDual capable of delivering both CD19 and EGFRvIII to GBM cells, and designed bispecific CAR-T and CAR-NK cells recognizing both targets simultaneously. This design addresses two issues at once: the OV expands the “visible” tumor range, while the bispecific CAR reduces dependence on a single antigen. This is particularly relevant for highly heterogeneous GBM.
Beyond target recognition, maintaining CAR cell function within the tumor is another critical challenge. OVs can be engineered to express immunomodulatory factors locally within the tumor, including IL-7, IL-12, IL-15, IL-21, CCL5, CXCL9, CXCL10, and CXCL11. In the team's multimodal GBM study, OV mIL15/21 provided membrane-bound IL-15 and IL-21 to support CAR-T and CAR-NK survival, expansion, and cytotoxicity locally. Thus, the complete therapeutic system can be understood as: OVDual addresses “who cannot be seen”; bispecific CAR addresses “who is recognized”; and OV mIL15/21 addresses “how to maintain function.”
The review also highlights CAR-NK cells as an emerging partner. Unlike CAR-T cells, CAR-NK cells can utilize both CAR-mediated targeting and natural NK receptor-mediated tumor killing. Off-the-shelf CAR-NK products derived from induced pluripotent stem cell platforms offer standardized, scalable manufacturing and rapid administration. This makes the combination of CAR-NK with OVs particularly attractive: OVs remodel the tumor, CAR-NK cells execute killing, and local cytokines further support sustained function.
The field is undergoing a conceptual transition from “combination therapy” to “systems engineering.” Early approaches treated OV plus CAR-T as a combination of two mechanistically distinct therapies. Next-generation designs are closer to OV × CAR-T/CAR-NK × immune modulation × delivery, with different modules addressing distinct bottlenecks. This means future OV–CAR therapy may not have a universal “standard combination” but should instead identify the dominant limiting factor for a given tumor and select virus and cell modules that address that specific limitation.
Despite the enormous potential of the OV–CAR platform, multiple key questions remain before broad clinical application. These include viral delivery and in vivo dissemination, treatment sequencing, and safety. Future clinical trials must not only assess whether treatment is effective but also answer: Does the virus truly infect the tumor? Is the payload successfully expressed? Do CAR cells truly enter the tumor and persist? Which module is actually contributing? “ These questions will require multidimensional biomarkers including longitudinal biopsies, circulating tumor DNA, viral DNA/RNA, cytokine profiles, single-cell sequencing, and spatial transcriptomics, ” the authors emphasize.
Looking ahead, OV–CAR platforms may further integrate multi-target CARs, synthetic Notch receptors, logic-gated CARs, off-the-shelf CAR-NK cells, and more precise viral engineering. An ideal therapeutic system might simultaneously possess modules for target installation, logic recognition, immune remodeling, cell fitness, safety control, and biomarker monitoring. Non-replicating platforms such as mRNA and lipid nanoparticles may also complement viral approaches as “pseudo-viral” immune modulation technologies.
In conclusion, when oncolytic viruses “board” CAR therapy, what changes is not merely the number of therapeutic agents but the design logic of tumor immunotherapy. “ Future OV – CAR therapy may no longer be a simple ‘virus plus cell therapy’ but a highly modular, programmable tumor immunology engineering system in which multiple therapeutic units operate in concert, ” the authors highlight. The key to next-generation solid tumor immunotherapy may not lie in finding a single therapy that solves all problems, but in designing treatment systems that precisely combine modules to overcome specific tumor barriers—allowing viruses to reshape the battlefield and CAR cells to execute precise attacks, ultimately establishing a sustainable, self-amplifying antitumor immune system within the tumor.
Reference
Title of original paper: When oncolytic viruses get on CAR: a synergic approach for solid tumor immunotherapy
Journal: Immunity & Inflammation
DOI: https://doi.org/10.1007/s44466-026-00055-z
About Immunity & Inflammation
Immunity & Inflammation is a newly launched open-access journal co-published by the Chinese Society for Immunology and Springer Nature under the leadership of Editors-in-Chief Prof. Xuetao Cao and Prof. Jules A. Hoffmann. Immunity & Inflammation aims to publish major scientific questions and cutting-edge advances that explore groundbreaking discoveries and insights across the spectrum of immunity and inflammation, from basic science to translational and clinical research.
Website: https://link.springer.com/journal/44466
About Professor Yanhong Shi from City of Hope National Medical Center, USA
Dr. Yanhong Shi is the Director of the Department of Neurodegenerative Diseases, Director of the Division of Stem Cell Biology Research, and the Herbert Horvitz Professor of Neuroscience at City of Hope National Medical Center. Her research focuses on stem cells and therapeutic approaches for neurodegenerative diseases.
Funding information
This work was supported by the National Cancer Institute of the National Institutes of Health under award number P30CA33572. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Immunity & Inflammation
Systematic review
Not applicable
When oncolytic viruses get on CAR: a synergic approach for solid tumor immunotherapy
15-Sep-2026
A patent on a multimodal therapy for cancer using oncolytic viruses has been filed by City of Hope.