CRISPR-mediated cancer therapies: Approaches to direct tumor targeting

CRISPR-Cas9 technologies have opened new possibilities for precision cancer treatment, addressing limitations inherent in conventional therapies such as chemotherapy and radiation. This review examines CRISPR-based strategies for direct tumor targeting, including oncogene inactivation, tumor suppressor gene reactivation, and tumor microenvironment (TME) modification. Key advances include KRAS^G12D inactivation via base editing, in which engineered deaminases introduce precise single-nucleotide changes without generating double-strand breaks; TP53 correction through homologous recombination, which uses a donor DNA template to repair mutant sequences at the targeted locus; and CDKN2A epigenetic remodeling using CRISPR-dCas9-TET1 demethylation, where catalytically inactive Cas9 guides the TET1 demethylase to hypermethylated promoters to restore gene expression. CRISPR screening has identified synthetic lethal interactions, such as PARP1 dependency in BRCA1^-/- tumors. TME editing strategies, including modification of cancer-associated fibroblasts, demonstrate enhanced antitumor responses. Delivery challenges are being addressed through viral vectors, including adenovirus, AAV, and lentivirus. Non-viral approaches include lipid nanoparticles, gold nanoparticles, exosomes, and stimuli-responsive systems such as MMP-cleavable and hypoxia-responsive nanoparticles. Clinical trials with CRISPR-engineered T-cells (e.g., CTX130) have demonstrated remission rates in hematologic malignancies. However, significant challenges remain, including cytokine release syndrome, immunotoxicity, tumor heterogeneity, and limited delivery efficiency in solid tumors. Overcoming these barriers requires interdisciplinary innovation, ethical oversight, and technological refinement to support the safe and effective integration of CRISPR-based strategies into precision oncology.