Cancer care has entered the era of precision oncology, where treatment decisions are increasingly guided by the molecular characteristics of individual tumors. Despite remarkable progress, many oncogenic drivers remain undruggable, and intrinsic or acquired resistance continues to limit the long-term effectiveness of targeted therapies and immunotherapy. These challenges have driven the search for technologies capable of intervening directly at the genetic level rather than simply targeting downstream proteins.
Among the most transformative advances is CRISPR-Cas, a programmable gene-editing platform that has rapidly evolved from an experimental laboratory tool into one of the most promising technologies in translational oncology. Originally developed for genome editing, CRISPR is now expanding into molecular diagnostics, functional genomics, immune-cell engineering, and early therapeutic applications, opening entirely new possibilities for precision cancer medicine.
In the Nature Reviews Clinical Oncology article “CRISPR in Clinical Oncology: Translational Advances from Molecular Diagnostics to Therapeutics,” Samuel Grigg, Carolyn Shembrey, Mohamed Fareh, Piers Blombery, Jacob E. Corn, John F. Seymour, and Joshua M. L. Casan describe how CRISPR technologies are reshaping multiple aspects of clinical oncology. Rather than functioning solely as a genome-editing tool, CRISPR has become a versatile platform capable of accelerating target discovery, improving molecular diagnostics, engineering next-generation immune cells, and enabling the first steps toward personalized in vivo gene editing.
In this editorial, we explore how CRISPR is transforming clinical oncology—from functional genomics and molecular diagnostics to engineered cellular immunotherapy and emerging in vivo therapeutic strategies. We also discuss the challenges that remain before widespread clinical implementation and how CRISPR may redefine the future of precision cancer therapy.
What Is CRISPR?
CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) is a programmable gene-editing technology that enables scientists to precisely target specific DNA or RNA sequences. Originally discovered as part of the adaptive immune defense system of bacteria against viral infections, CRISPR has evolved into one of the most powerful molecular platforms in modern biomedical research.
Unlike conventional therapies that primarily target proteins, CRISPR acts directly at the genetic level, allowing researchers to disrupt, repair, replace, or regulate disease-associated genes with remarkable precision. Beyond genome editing, CRISPR has become an essential tool for functional genomics, molecular diagnostics, and immune-cell engineering, extending its applications far beyond basic laboratory research.
As highlighted by Grigg and colleagues, CRISPR is no longer viewed as a single genome-editing technology but as a modular platform capable of nucleic acid targeting, precise sequence editing, targeted gene regulation, and molecular diagnostics. These capabilities are positioning CRISPR as one of the most versatile technologies driving the next generation of precision oncology.
From Functional Genomics to Therapeutic Discovery
One of the earliest and most influential applications of CRISPR in oncology has been functional genomics. Unlike conventional molecular approaches that investigate one gene at a time, CRISPR-based screening enables systematic interrogation of thousands of genes simultaneously, providing unprecedented insight into the molecular mechanisms that drive cancer initiation, progression, metastasis, and therapeutic resistance.
In their review, Grigg and colleagues describe how genome-wide CRISPR-Cas screening has transformed cancer target discovery. Functional perturbation screens allow investigators to identify cancer dependencies, synthetic lethal interactions, and mechanisms of resistance to targeted therapies and immunotherapy. These approaches also facilitate the identification of rational drug combinations capable of overcoming therapeutic resistance.
Rather than simply validating existing biological pathways, CRISPR enables researchers to uncover previously unrecognized therapeutic vulnerabilities, accelerating the discovery of novel treatment strategies and expanding the landscape of precision oncology.
CRISPR Is Transforming Molecular Diagnostics
Although CRISPR is widely recognized for its genome-editing capabilities, its diagnostic applications are advancing just as rapidly. By exploiting highly specific nucleic acid recognition, CRISPR-based diagnostic platforms enable rapid detection of cancer-associated mutations with remarkable sensitivity and specificity.
According to Grigg and colleagues, these technologies convert precise DNA or RNA sequence recognition into fast molecular diagnostics capable of identifying actionable mutations, supporting liquid biopsy analysis, and monitoring disease evolution. Compared with conventional molecular assays, CRISPR-based diagnostics have the potential to reduce turnaround time while requiring less laboratory infrastructure.
As molecular profiling becomes increasingly central to precision oncology, CRISPR-based diagnostics may expand opportunities for minimal residual disease detection, longitudinal monitoring of circulating tumor DNA, and early identification of treatment resistance.
Engineering the Next Generation of Cancer Immunotherapy
Perhaps the most advanced clinical application of CRISPR is ex vivo immune-cell engineering. Instead of editing tumors directly within the patient, immune cells are genetically modified outside the body before expansion and reinfusion.
Grigg and colleagues highlight that current clinical translation has focused primarily on gene-edited CAR-T cells and T-cell receptor (TCR)-engineered lymphocytes, with the goal of improving persistence, enhancing antitumor activity, and increasing resistance to immunosuppressive signals within the tumor microenvironment. CRISPR also enables disruption of inhibitory immune pathways and supports the development of allogeneic “off-the-shelf” cellular therapies.
These advances illustrate a fundamental shift in cancer immunotherapy. Rather than developing entirely new immune-cell platforms, CRISPR enhances existing cellular therapies by making them more programmable, durable, and capable of overcoming mechanisms of tumor immune escape.
Toward In Vivo Precision Gene Editing
While ex vivo immune-cell engineering has already entered clinical translation, the next frontier is in vivo CRISPR therapy, in which gene editing occurs directly within the patient.
Instead of modifying cells outside the body, in vivo approaches seek to deliver CRISPR systems directly to tumors or specific immune-cell populations, enabling selective editing of oncogenic mutations, fusion genes, or resistance-associated pathways. Such strategies have the potential to expand therapeutic options for cancers driven by genetic alterations that remain inaccessible to conventional pharmacological approaches.
However, Grigg and colleagues emphasize that widespread clinical implementation will depend on overcoming several major challenges, including efficient in vivo delivery, minimizing off-target editing, limiting immunogenicity, and ensuring long-term genomic safety. Advances in delivery technologies, including lipid nanoparticles and other non-viral systems, are expected to play a critical role in translating these approaches into routine clinical practice.
Challenges and Future Directions
Despite remarkable progress, important scientific and regulatory challenges continue to shape the future of CRISPR in oncology. According to Grigg and colleagues, improving editing specificity, reducing off-target effects and structural genomic alterations, optimizing delivery systems, and addressing immunogenicity remain among the highest priorities for clinical translation.
The authors also highlight that the future of CRISPR extends well beyond conventional genome editing. Emerging technologies—including base editing, prime editing, RNA editing, and programmable gene regulation—are expanding the range of therapeutic possibilities while potentially reducing the risks associated with double-strand DNA breaks.
As these technologies continue to mature, CRISPR is expected to become an integrated component of precision oncology, supporting molecular diagnostics, functional genomics, immune-cell engineering, and personalized therapeutic interventions. Rather than representing a single breakthrough, CRISPR is laying the foundation for a new generation of programmable cancer therapies capable of addressing some of oncology’s most challenging unmet needs.
Expert Perspective: The Future of CRISPR in Precision Oncology
To complement the current evidence, OncoDaily IO invited Dr. Daniel Lempkovitz Manor, Clinical Director at LBT Lasers, São Paulo, Brazil, to share his perspective on how CRISPR-based gene editing could reshape the future of cancer immunotherapy and precision oncology.
How do you envision the future relationship between CRISPR-based gene editing and cancer immunotherapy?
“I believe CRISPR and cancer immunotherapy will increasingly become two components of the same therapeutic system. Immunotherapy provides the cellular machinery capable of finding and killing cancer, while CRISPR can reprogram that machinery to function inside the hostile environment of a solid tumor.
Ex vivo editing could generate TILs, CAR-T, TCR-T, NK cells, and macrophages that are more resistant to exhaustion, metabolic stress, and suppressive signals such as TGF-β. In vivo editing could go further by modifying immune cells directly inside the patient or selectively disrupting oncogenic dependencies and immune-evasion pathways within the tumor.
However, CRISPR alone will not overcome tumor heterogeneity. The future will probably require multiplexed and sequential treatment: molecularly map every relevant clone, edit selected vulnerabilities, induce immunogenic tumor destruction, improve antigen presentation, and then deploy polyclonal or multi-target immunity against the surviving disease.
The FDA approval of lifileucel has already demonstrated that tumor-derived polyclonal T cells can produce clinically meaningful responses in metastatic solid cancer. The next step is to make these cells more programmable, persistent, and resistant to suppression through gene editing.”
What role could in vivo CRISPR gene editing play in overcoming resistance to cancer immunotherapy?
“In vivo CRISPR could address resistance at several biological levels simultaneously.
Within cancer cells, it could disrupt oncogenic drivers, antigen-loss mechanisms, defective antigen-presentation pathways, and genes responsible for resistance to immune-mediated killing. Within immune cells, it could transiently or permanently remove inhibitory programs, improve trafficking, preserve memory, and increase resistance to exhaustion. It may also become possible to edit stromal, vascular, and myeloid compartments that physically or biologically exclude T cells from the tumor.
The central challenge is delivery. Editing must reach the correct cell type, at the correct anatomical site, and at a clinically meaningful proportion, without producing unacceptable off-target or systemic effects. Therefore, targeted lipid nanoparticles and other non-viral delivery systems may ultimately be as important as the editing enzyme itself.
I do not see in vivo CRISPR as a one-time universal intervention. I see it as an adaptive tool: ctDNA, single-cell, and spatial analysis would identify the dominant resistance mechanism, a targeted editing payload would address it, and the tumor would then be remapped to detect the next emerging clone.”
Which component of the tumor microenvironment represents the most promising target for CRISPR-based gene editing, and why?
“Rather than selecting only one suppressive cell population, I would prioritize the antigen-presentation and immune-trafficking axis, particularly cDC1 dendritic cells together with the tumor vasculature.
cDC1 cells are essential for cross-presenting tumor antigens and initiating effective CD8-positive T-cell responses. Even the most powerful CAR-T, TIL, or checkpoint therapy will remain limited if tumor antigens are not efficiently captured, presented, and converted into systemic immunity. Recent research showing that CARM1 inhibition can improve cDC1 activation and cross-presentation illustrates how epigenetic reprogramming of this compartment may amplify vaccines and immunotherapy.
The vasculature is equally important because it controls whether immune cells can enter metastatic niches. Research from the DKFZ suggesting that specialized liver endothelial cells can cross-present tumor antigens indicates that blood vessels are not merely passive conduits; they can participate directly in immune surveillance.
Therefore, the ideal strategy may be to edit or reprogram dendritic, endothelial, and myeloid cells together: improve antigen presentation, normalize immune trafficking, reduce TGF-β-driven exclusion, and convert an immunologically “cold” tumor into an accessible and inflamed target.”
Looking ahead, what breakthrough do you believe will define the future of CRISPR-based cancer therapy?
“The defining breakthrough will not be a more powerful nuclease alone. It will be cell-selective, multiplexed, and controllable in vivo delivery.
Once we can deliver CRISPR, base editors, prime editors, or gene-regulating systems specifically to malignant cells, T cells, dendritic cells, macrophages, or tumor endothelium, cancer therapy may become a programmable and iterative process rather than a fixed treatment.
My long-term vision is an integrated eradication system: map every malignant clone with single-cell, spatial, and ctDNA technologies → block its oncogenic and metastatic drivers → use CRISPR or RNA therapeutics to remove resistance mechanisms → target heterogeneous antigens with multi-target ADCs → weaken DNA repair → induce precise and immunogenic tumor destruction → improve antigen presentation → deploy TILs, bispecific engagers, engineered CAR-T, NK cells, and macrophages → monitor molecular residual disease → redesign and repeat before relapse.
Platforms under investigation already represent individual components of this architecture, including targeted CRISPR delivery associated with Dan Peer’s nanomedicine research, the broader genome-editing ecosystem developed by Jennifer Doudna and the Innovative Genomics Institute, TIL therapy from Iovance, programmable T-cell platforms such as ArsenalBio, bispecific and in vivo immune-engineering approaches, and therapies such as Onchilles Pharma’s N17350, which is being studied for selective cancer killing and immunogenic cell death. Although N17350 has entered early clinical evaluation, its systemic immune effects still require confirmation in patients.
The ultimate objective is not simply to shrink the visible tumor. It is to eliminate every primary, metastatic, and molecularly residual clone while creating durable immune surveillance against recurrence.
This is not yet a proven universal cure. But I believe it is a credible blueprint for how curative therapy may eventually be engineered—not through one technology, but through the coordinated integration of precise gene editing, targeted delivery, tumor microenvironment reprogramming, and multilayer immunity.”