CRISPR technologies have revolutionized genome editing, yet challenges remain, particularly in immunocompetent models. Saini et al. highlight the limitations of conventional CRISPR-Cas9 tools in vivo, where immunogenicity can lead to clonal dropouts, thus compromising target identification in cancer research (ref: Saini doi.org/10.1016/j.cell.2025.10.007/). In a Phase 1 trial, Laffin et al. demonstrated the safety and efficacy of CTX310, a CRISPR-Cas9 mRNA targeting ANGPTL3, with no dose-limiting toxic effects observed in 15 participants (ref: Laffin doi.org/10.1056/NEJMoa2511778/). Fanton et al. introduced engineered recombinases for site-specific DNA insertion, addressing the low efficiency and high off-target activity of large serine recombinases, thus paving the way for more precise genomic modifications (ref: Fanton doi.org/10.1038/s41587-025-02895-3/). Liu et al. developed CRISPR PRO-LiveFISH, enabling live-cell imaging of chromatin dynamics and enhancer interactions, showcasing the potential of CRISPR for real-time genomic studies (ref: Liu doi.org/10.1038/s41587-025-02887-3/). McDiarmid et al. compiled a parts list of promoters and gRNA scaffolds, identifying thousands of sequences that enhance genome editing efficiency in mammalian systems (ref: McDiarmid doi.org/10.1038/s41587-025-02896-2/). The theme also includes studies on metagenomic editing using CRISPR-associated transposases (Gelsinger et al., ref: Gelsinger doi.org/10.1126/science.adx7604/) and the development of metabolite-responsive scaffold RNAs for dynamic transcriptional regulation (Stohr et al., ref: Stohr doi.org/10.1093/nar/).

Cancer genomics has unveiled critical insights into therapeutic resistance and mutation dynamics. Zhang et al. identified a Paneth-like transition in colorectal cancer cells that confers resistance to dual KRAS and EGFR targeting, emphasizing the need for novel therapeutic strategies (ref: Zhang doi.org/10.1016/j.ccell.2025.10.010/). Boscenco et al. reported recurrent mutations in mitochondrial ribosomal RNA genes across 14,106 tumor genomes, suggesting a significant role of these mutations in cancer biology (ref: Boscenco doi.org/10.1038/s41588-025-02374-0/). Li et al. utilized genome-scale CRISPR screens to discover PTGES3 as a modulator of androgen receptor function in prostate cancer, highlighting the potential for targeted therapies (ref: Li doi.org/10.1038/s41588-025-02388-8/). In triple-negative breast cancer, Zhang et al. explored immune evasion mechanisms, revealing the role of FAM114A1 in resistance to immunotherapy (ref: Zhang doi.org/10.1038/s41392-025-02472-9/). Sun et al. identified TRIM25 as a regulator of VISTA, a promising target for enhancing cancer immunotherapy (ref: Sun doi.org/10.1038/s41422-025-01186-5/). Tiek et al. investigated cysteine addiction in glioblastoma, proposing selenium compounds as therapeutic agents against drug resistance (ref: Tiek doi.org/10.1093/neuonc/).

Gene editing technologies are increasingly applied to model and treat diseases. Golden et al. developed a knock-in model enabling the switch between APOE4 and APOE2 alleles in mice, demonstrating improvements in Alzheimer's disease-related metabolic signatures and cognition (ref: Golden doi.org/10.1038/s41593-025-02094-y/). He et al. conducted CRISPR screening in gastric organoids to identify tumor suppressors, revealing critical insights into gastric cancer biology (ref: He doi.org/10.1053/j.gastro.2025.09.009/). Kohne et al. examined the role of DNMT3A R882H mutations in acute myeloid leukemia, finding that these mutations are not essential for disease maintenance but are associated with increased leukemia stem cell frequency (ref: Köhnke doi.org/10.1158/2159-8290.CD-24-1604/). Hardouin et al. focused on base editing to correct β-thalassemia-causing mutations, showcasing the potential of gene therapy in treating genetic disorders (ref: Hardouin doi.org/10.1126/scitranslmed.adt8617/).

Synthetic biology leverages genetic engineering for innovative applications. McDiarmid et al. provided a comprehensive parts list of promoters and gRNA scaffolds, enhancing the toolkit available for mammalian genome engineering (ref: McDiarmid doi.org/10.1038/s41587-025-02896-2/). Stohr et al. introduced metabolite-responsive scaffold RNAs, enabling dynamic transcriptional regulation and expanding the potential for creating responsive biosystems (ref: Stohr doi.org/10.1093/nar/). Nakamura et al. developed RNA-guided green fluorescent proteins for programmable RNA imaging, demonstrating the versatility of CRISPR technology in molecular analysis (ref: Nakamura doi.org/10.1093/nar/). Jang et al. presented a CRISPR/Cas12a2-based method for ultra-sensitive RNA detection, emphasizing the diagnostic potential of CRISPR technologies (ref: Jang doi.org/10.1093/nar/).

Immunotherapy has transformed cancer treatment, yet resistance mechanisms pose significant challenges. Zhang et al. explored the role of FAM114A1 in orchestrating immune evasion in triple-negative breast cancer, highlighting the need for targeted strategies to overcome resistance (ref: Zhang doi.org/10.1038/s41392-025-02472-9/). Tiek et al. investigated cysteine addiction in drug-resistant glioblastoma, proposing novel therapeutic approaches using selenium compounds to target metabolic vulnerabilities (ref: Tiek doi.org/10.1093/neuonc/). Sun et al. identified TRIM25 as a positive regulator of VISTA, suggesting that targeting this pathway could enhance the efficacy of immunotherapies (ref: Sun doi.org/10.1038/s41422-025-01186-5/). Doherty et al. examined the diversity of viral phosphodiesterases as a mechanism for immune signaling evasion, providing insights into viral strategies against host defenses (ref: Doherty doi.org/10.1016/j.chom.2025.10.018/).

Microbial engineering is advancing through innovative CRISPR applications. Gelsinger et al. introduced Metagenomic Editing (MetaEdit), a platform for modifying commensal bacteria in vivo, showcasing its potential for microbiome engineering (ref: Gelsinger doi.org/10.1126/science.adx7604/). Zhang et al. highlighted the Paneth-like transition in colorectal cancer cells, which contributes to resistance against dual KRAS and EGFR targeting, emphasizing the interplay between microbial dynamics and cancer therapy (ref: Zhang doi.org/10.1016/j.ccell.2025.10.010/). Johnson et al. described a phage-encoded anti-CRISPR protein that co-opts host enolase to evade CRISPR immunity, illustrating the arms race between phages and bacterial defenses (ref: Johnson doi.org/10.1038/s41564-025-02178-2/).

Advancements in RNA technologies are enhancing our understanding of RNA modifications and their implications. Lin et al. established RMPore, a database for single-molecule RNA modifications detected by Nanopore sequencing, facilitating the exploration of post-transcriptional regulation (ref: Lin doi.org/10.1093/nar/). Bao et al. updated RM2Target, a database linking RNA modification proteins to their target genes, addressing the growing complexity of RNA modification research (ref: Bao doi.org/10.1093/nar/). Stohr et al. developed metabolite-responsive scaffold RNAs for dynamic CRISPR transcriptional regulation, expanding the toolkit for RNA-based biosensors (ref: Stohr doi.org/10.1093/nar/). Liu et al. presented a method for profiling circRNAs using CRISPR-Cas12a, demonstrating the potential for targeted RNA detection in cancer research (ref: Liu doi.org/10.1093/nar/).

Understanding cellular and molecular mechanisms in cancer is crucial for developing effective therapies. Boscenco et al. reported recurrent mutations in mitochondrial ribosomal RNA genes, suggesting their role in tumorigenesis and potential as therapeutic targets (ref: Boscenco doi.org/10.1038/s41588-025-02374-0/). Tiek et al. explored cysteine addiction in drug-resistant glioblastoma, proposing that targeting redox pathways could enhance treatment efficacy (ref: Tiek doi.org/10.1093/neuonc/). Tang et al. identified a PERK/MAT2A/PDGFB axis that supports the survival of circulating tumor cell clusters, highlighting the adaptive mechanisms that facilitate metastasis (ref: Tang doi.org/10.1002/cac2.70072/). Hardouin et al. focused on base editing to correct β-thalassemia-causing mutations, showcasing the potential of gene therapy in addressing genetic disorders (ref: Hardouin doi.org/10.1126/scitranslmed.adt8617/).