Cancer care is increasingly driven by molecular classification, yet many key oncogenic drivers remain undruggable, and intrinsic or acquired resistance to treatment frequently limits durable clinical benefit. CRISPR–Cas technologies provide a modular, programmable platform to interrogate and directly manipulate cancer biology via sequence-specific targeting of DNA or RNA and have advanced from experimental tools to the early stages of clinical translation. In this Review, we outline how CRISPR-enabled functional genomics approaches can reveal unexpected cancer dependencies and resistance mechanisms. We discuss emerging applications of CRISPR-based diagnostics in oncology that convert precise nucleic acid sequence recognition into rapid mutation detection. We also discuss applications of CRISPR in therapeutic strategies ranging from ex vivo immune cell engineering to nascent in vivo interventions that directly target tumour-related sequences such as fusion junctions or single-nucleotide variants. Finally, we highlight technological and regulatory challenges, including effective delivery of the editing machinery to cells in vivo, safety and platform-level regulatory frameworks, that will determine the clinical utility of CRISPR-based diagnostics and therapies in oncology.
Cancer care is increasingly driven by molecular classification, yet many key oncogenic drivers remain undruggable, and intrinsic or acquired resistance to treatment frequently limits durable clinical benefit. CRISPR–Cas technologies provide a modular, programmable platform to interrogate and directly manipulate cancer biology via sequence-specific targeting of DNA or RNA and have advanced from experimental tools to the early stages of clinical translation. In this Review, we outline how CRISPR-enabled functional genomics approaches can reveal unexpected cancer dependencies and resistance mechanisms. We discuss emerging applications of CRISPR-based diagnostics in oncology that convert precise nucleic acid sequence recognition into rapid mutation detection. We also discuss applications of CRISPR in therapeutic strategies ranging from ex vivo immune cell engineering to nascent in vivo interventions that directly target tumour-related sequences such as fusion junctions or single-nucleotide variants. Finally, we highlight technological and regulatory challenges, including effective delivery of the editing machinery to cells in vivo, safety and platform-level regulatory frameworks, that will determine the clinical utility of CRISPR-based diagnostics and therapies in oncology.
CRISPR–Cas has evolved from a laboratory genome editing tool into a modular, programmable platform for nucleic acid targeting, precise sequence installation and targeted gene regulation.
Functional CRISPR–Cas-based gene-perturbation screens enable mapping of cancer dependencies, resistance mechanisms and synthetically lethal interactions, identifying targets and rational combination strategies for therapy development.
Diagnostics based on CRISPR–Cas collateral cleavage activity enable rapid, low-infrastructure-requirement nucleic acid detection for mutation calling and liquid biopsy-based monitoring but remain comparatively underdeveloped in oncology.
With regard to CRISPR–Cas-based therapies, clinical translation efforts to date have centred on ex vivo cell engineering, including gene-edited T cell and CAR T cell products designed to have enhanced persistence, potency and resistance to tumour immunosuppression.
CRISPR–Cas systems are poised to enable personalized, precision intervention at the DNA or RNA level, potentially extending therapeutic reach beyond conventional protein druggability constraints.
Clinical implementation will depend on addressing safety and feasibility, including off-target editing and structural variant risks, in vivo delivery constraints, immunogenicity and interpatient genetic heterogeneity.
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