Solid tumors have long been the stubborn frontier of cell-based immunotherapy. While chimeric antigen receptor (CAR) T cells have transformed outcomes in certain blood cancers, their performance inside solid tumors has repeatedly fallen short of expectations. A new review led by Professor Yanhong Shi and Dr. Jia Li at City of Hope National Medical Center, published on September 15, 2026, in Volume 2 of the journal Immunity & Inflammation, argues that the missing ingredient may not be a better CAR cell alone, but a partner capable of reshaping the tumor itself. The authors propose that oncolytic viruses (OVs) and CAR-based cells should not be viewed as two separate drugs administered together, but as modules of a single, co-designed, self-amplifying therapeutic system that operates continuously within the tumor microenvironment.
The rationale begins with the specific barriers that defeat CAR cells in solid malignancies. Target antigens on solid tumors display marked spatial and temporal heterogeneity, meaning that different regions of the same tumor, and different stages of its evolution, present different molecular surfaces. When CAR cells exert continuous selective pressure, low-antigen or antigen-negative subpopulations can become enriched, a phenomenon known as antigen escape. Physical barriers compound the problem: abnormal vasculature, dense extracellular matrix, and complex tissue architecture impede the infiltration of transferred cells. Even after CAR cells gain entry, the tumor microenvironment confronts them with hypoxia, nutrient deprivation, immunosuppressive cytokines such as TGF-β, immune checkpoints, and tumor-associated myeloid cells, all of which drive functional exhaustion. The review notes that these challenges are particularly pronounced in glioblastoma (GBM), one of the most immunologically hostile solid tumors.
Oncolytic viruses offer a way to attack these barriers from within. These engineered viruses selectively infect and replicate inside tumor cells, triggering immunogenic cell death. The lytic cycle releases a potent array of tumor-associated antigens along with pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), including ATP, HMGB1, calreticulin, and double-stranded DNA and RNA. These danger signals activate local antigen-presenting cells and induce robust inflammatory cytokine and chemokine gradients, recruiting dendritic cells, macrophages, natural killer cells, and endogenous T cells. In effect, viral oncolysis converts a cold, suppressive tumor microenvironment into an active site of immune amplification. The review emphasizes that this immune-remodeling function, rather than direct tumor cell killing alone, is where the true value of OVs lies for combination design.
Central to the authors’ argument is the concept of a self-amplifying circuit that links viral lysis to CAR-mediated killing. As they describe it, OV infection leads to tumor lysis and the 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. Each round of destruction supplies fresh targets and inflammatory context for the next. This dynamic, multistep engineered circuit is what distinguishes the OV–CAR platform from simple additive drug combinations, in which two agents act through independent mechanisms without reinforcing one another. The tumor becomes, in the authors’ framing, a site where the therapy continuously regenerates its own momentum.
One of the most striking engineering strategies addresses the problem of missing or heterogeneous CAR targets directly. OVs can be engineered to deliver payloads that force infected tumor cells to express new surface antigens, such as truncated CD19, a molecule normally associated with B-cell malignancies. This temporarily converts CD19-negative solid tumor cells into CD19-positive targets recognizable by CAR-T cells. The elegance of the approach lies in how it separates two distinct problems: the virus determines where to install the target, while the CAR determines how to kill the marked cell. Antigen installation becomes a programmable function of the viral module rather than a fixed property of the tumor, fundamentally changing the calculus of target selection in solid tumors.
Building on this concept, the City of Hope team constructed an engineered OV, designated OVDual, capable of delivering both CD19 and EGFRvIII to GBM cells, and designed bispecific CAR-T and CAR-NK cells that recognize both targets simultaneously. This dual-module design tackles two issues at once: the virus expands the visible range of the tumor by installing antigens on infected cells, while the bispecific CAR reduces dependence on any single antigen, blunting the risk of escape through loss of one target. For a tumor as heterogeneous as glioblastoma, where antigen expression varies dramatically across regions and over time, this layered redundancy is particularly relevant. The strategy illustrates how viral and cellular modules can be matched to one another rather than selected independently.
Target recognition, however, is only half the battle; maintaining CAR cell function inside the tumor is another critical challenge. OVs can be engineered to express immunomodulatory factors locally, including IL-7, IL-12, IL-15, IL-21, CCL5, CXCL9, CXCL10, and CXCL11, converting the tumor itself into a local support factory for transferred cells. In the team’s multimodal GBM study, an OV expressing membrane-bound IL-15 and IL-21, termed OV mIL15/21, provided localized cytokine support to sustain CAR-T and CAR-NK survival, expansion, and cytotoxicity. The complete therapeutic system can therefore be understood as a division of labor: OVDual addresses who cannot be seen, the bispecific CAR addresses who is recognized, and OV mIL15/21 addresses how to maintain function under hostile conditions.
The review also highlights CAR-NK cells as an emerging partner for viral platforms. Unlike CAR-T cells, CAR-NK cells can kill through both CAR-mediated targeting and natural NK receptor-mediated recognition, providing an additional, antigen-independent killing mechanism. Off-the-shelf CAR-NK products derived from induced pluripotent stem cell platforms offer standardized, scalable manufacturing and rapid administration, advantages that align well with the logistics of viral combination therapy. In this configuration, OVs remodel the tumor, CAR-NK cells execute killing through parallel pathways, and locally delivered cytokines sustain the cellular component over time. The convergence of scalable NK manufacturing and programmable viral payloads may prove one of the most practically translatable directions in the field.
Conceptually, the authors describe the field as undergoing a transition from combination therapy to systems engineering. Early approaches treated OV plus CAR-T as the pairing of two mechanistically distinct treatments. Next-generation designs instead resemble a multiplicative architecture of virus, CAR-T or CAR-NK cells, immune modulation, and delivery, with different modules addressing distinct bottlenecks. This implies that future OV–CAR therapy may never settle on a single universal standard combination. Instead, clinicians would identify the dominant limiting factor for a given tumor, whether antigen heterogeneity, poor infiltration, or functional exhaustion, and select the virus and cell modules that specifically address that limitation. Therapy design becomes diagnostic and modular rather than one-size-fits-all.
Significant questions remain before broad clinical application. Viral delivery and in vivo dissemination, treatment sequencing, and safety all require rigorous answers. Future trials, the authors stress, must go beyond measuring whether a treatment works and ask whether the virus truly infects the tumor, whether the payload is successfully expressed, whether CAR cells genuinely enter and persist within the lesion, and which module is actually contributing to the effect. Answering these questions will require multidimensional biomarkers, including longitudinal biopsies, circulating tumor DNA, viral DNA and RNA detection, cytokine profiling, single-cell sequencing, and spatial transcriptomics. Looking further ahead, the platform may integrate multi-target CARs, synthetic Notch receptors, logic-gated CARs, off-the-shelf CAR-NK cells, and more precise viral engineering, while non-replicating technologies such as mRNA and lipid nanoparticles may complement viral approaches as pseudo-viral immune modulators. The authors’ conclusion is that the future of solid tumor immunotherapy may lie not in a single therapy that solves every problem, but in programmable systems in which viruses reshape the battlefield and CAR cells execute precise, self-reinforcing attacks. A patent on a multimodal oncolytic virus cancer therapy has been filed by City of Hope, and the work was supported in part by the National Cancer Institute under award number P30CA33572.
Subject of Research: Combining oncolytic viruses with CAR-T and CAR-NK cell therapy to overcome resistance barriers in solid tumors
Article Title: Oncolytic viruses and car cells: A modular platform to overcome solid tumor barriers
Article References: Oncolytic viruses and car cells: A modular platform to overcome solid tumor barriers. (n.d.). Original publication
Image Credits: AI Generated
DOI: Not provided
Keywords: oncolytic viruses, CAR-T cells, CAR-NK cells, solid tumors, glioblastoma, tumor microenvironment, antigen heterogeneity, immunotherapy, immunogenic cell death, cytokines, bispecific CAR, systems engineering
