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

The five recipients are Dr. Waseem Abbas, assistant professor of systems engineering; Dr. Sourav Dutta, assistant professor of electrical and computer engineering; Dr. Kirill Lazebnik, assistant professor of mathematical sciences; Dr. Kyle McCall, assistant professor of materials science and engineering; and Dr. Xinda Wang, assistant professor of computer science. Four of the five, Abbas, Dutta, McCall and Wang, are members of the university’s Erik Jonsson School of Engineering and Computer Science, while Lazebnik belongs to the School of Natural Sciences and Mathematics. The portfolio of funded work illustrates how the CAREER mechanism can seed progress across the full stack of modern technology, from the atoms inside a transistor to the mathematical abstractions that describe dynamical behavior and the code that keeps the world’s software infrastructure safe.

University research leadership framed the awards as evidence of the institution’s growing strength in areas that will define the coming decades of technology. “From resilient networks and advanced semiconductors to artificial intelligence, cybersecurity and fundamental mathematics, these researchers are tackling complex challenges with the potential to shape the technologies and systems of the future,” said Dr. Joseph Pancrazio, vice president for research and innovation and professor of bioengineering. He emphasized that the awards also recognize the recipients’ commitment to integrating research and education, giving students the chance to learn through hands-on discovery and helping cultivate the next generation of researchers and innovators. That educational component is not incidental to the CAREER program; it is a core evaluation criterion, and each of the five UT Dallas projects embeds training, outreach or curriculum development alongside the technical work.

Dr. Waseem Abbas received a five-year award of $514,916 to confront one of the most consequential questions in networked engineering: what happens when a system designed to absorb disruption is hit by something worse. Robot teams, infrastructure networks and distributed computing systems, in which tasks are shared across many devices, are typically engineered with a certain tolerance for failure built in. If an attack, fault or environmental disturbance stays within that expected envelope, the system degrades gracefully. But when the disruption exceeds the threshold, performance can deteriorate rapidly and unpredictably, sometimes collapsing in ways that cascade through the entire network. Abbas aims to develop networked systems that adapt as conditions worsen, so that performance declines smoothly rather than failing catastrophically. A second strand of his research seeks to identify the most critical connections and components within a network, the nodes and links whose protection yields the greatest resilience. By concentrating defenses on those essential elements, operators could maintain core functions without paying for costly, blanket redundancy across every part of the system. The work has obvious implications for autonomous vehicle coordination, industrial automation and the distributed computing fabric that increasingly underpins everyday services.

Dr. Sourav Dutta’s award, totaling $501,234, targets the physical bottleneck that threatens to slow the artificial intelligence revolution: the semiconductor itself. As AI models and autonomous systems generate staggering volumes of data, conventional computer chips struggle to move information efficiently between the separate regions where data is stored, processed and transmitted. Every transfer across those internal distances costs energy and time, and at the scale of modern workloads the cost becomes prohibitive. Dutta will investigate ultrathin oxide semiconductor transistors with a property that could prove transformative: they can be manufactured at low temperatures and stacked vertically on top of conventional silicon electronics. Vertical stacking would shorten the distance data must travel, directly reducing energy consumption and potentially enabling faster, more efficient chips. Because the low-temperature fabrication process is compatible with existing silicon technology, the approach could be integrated with current manufacturing rather than requiring an entirely new industrial base. Dutta also plans to apply artificial intelligence and computational modeling to predict how candidate transistors will perform before they are built, accelerating design cycles and shrinking the optimization process that normally stretches across years of laboratory iteration.

On the software side of the engineering school, Dr. Xinda Wang received $617,397 to build AI tools that can help open-source software communities catch security vulnerabilities earlier, at the moment developers are making changes to code. Open-source software, assembled from publicly available code that anyone can inspect, contribute to or reuse, has become the invisible backbone of the digital world. It powers commercial products, government systems and critical infrastructure alike. That ubiquity carries a hidden risk: when a vulnerability exists in a widely used open-source component, it silently propagates into every downstream system that incorporates the original code, multiplying the potential blast radius of a single flaw. Wang’s team will train machine-learning systems to recognize patterns in how code changes are made and how those changes ripple through other parts of a software project, flagging suspicious modifications before they are merged and deployed. Just as importantly, the researchers will develop AI models capable of explaining why a particular change may pose a security risk. That explanatory capability matters because security teams and volunteer maintainers often operate with limited time and resources; a tool that simply raises an alarm without context is easily ignored, while one that articulates its reasoning can be trusted and acted upon.

The fourth engineering awardee, Dr. Kyle McCall, received the largest of the five grants, $796,646, to probe a question that sits at the frontier of materials science: how the local atomic structure of emerging semiconductor materials determines their properties and their potential in electronics and energy technologies. Many of the most promising new materials exhibit unusual behavior that arises from deviations of atoms away from their ideal, expected positions within the crystal lattice. These local structural distortions can dramatically alter how a material conducts, absorbs light or responds to electric fields, yet scientists do not fully understand how the deviations can be controlled through the composition and arrangement of the constituent atoms. Compounding the challenge, the distortions are invisible to conventional characterization techniques, which average over large regions and therefore miss the local disorder that matters most. McCall and his team will use total X-ray scattering, a technique sensitive to how atoms are locally bonded within a material, to map the relationship between chemical composition, atomic deviations and resulting properties. The ultimate goal is a set of design principles that researchers can use to create new semiconductor materials with desirable properties on demand. The project also carries an educational mission, providing undergraduates with hands-on research experience and developing educational resources for teachers and students across the Dallas-Fort Worth region.

The lone recipient in the School of Natural Sciences and Mathematics, Dr. Kirill Lazebnik, secured a $450,000 CAREER grant for work in pure mathematics with unusually broad applied reach. His research concerns rational functions, the mathematical objects formed as ratios of polynomials, which serve as fundamental tools for mathematicians, scientists and engineers who model and analyze complex systems. Rational functions appear throughout signal processing, dynamical systems and scientific computing, making advances in their theory potentially consequential far beyond mathematics departments. Lazebnik’s project aims to deepen understanding of the structure of the space of rational functions and to explore how these functions might be applied in additional areas of analysis and dynamics. Questions that sound abstract, such as how the space of such functions is organized and connected, often translate into practical insight for engineers studying stability, control and signal behavior. Like his colleagues, Lazebnik has built education into the heart of the grant, with undergraduate research opportunities and community outreach programs designed to train future mathematicians and widen access to the discipline.

Taken together, the five awards reveal a coherent picture of where foundational research investment is flowing and why. The problems the CAREER recipients have chosen sit precisely at the pressure points of contemporary technology: networks that must survive deliberate attack and random failure, chips that must move data without drowning in their own energy consumption, software supply chains that must be defended at the moment of change, materials whose properties are hidden in atomic-scale disorder, and mathematical structures that underpin our ability to model all of the above. Each project also treats education as an engineering problem in its own right, designing pipelines of trained students, teacher resources and community engagement that extend the impact of the research well beyond the laboratory. For UT Dallas, the sweep of the awards across two schools signals institutional momentum in fields where competition for federal support is fierce. For the researchers themselves, five years of stable funding at the start of an academic career is a rare luxury, the freedom to pursue ambitious, long-horizon questions, and to bring students along for the entire journey from first hypothesis to published result.

Subject of Research: 2026 NSF CAREER awards to five UT Dallas faculty supporting research on network resilience, oxide semiconductor transistors, open-source software security, atomic structure of semiconductor materials and rational functions.

Article Title: Technologies, math research get lift from CAREER awards

Article References: Technologies, math research get lift from CAREER awards. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: NSF CAREER awards, University of Texas at Dallas, network resilience, oxide semiconductor transistors, open-source software security, artificial intelligence, semiconductor materials, total X-ray scattering, rational functions, systems engineering, materials science, mathematical sciences