Recent advancements in gene editing techniques have significantly enhanced our understanding and manipulation of genetic material across various organisms. A notable study by Hein et al. introduced a high-resolution strategy for mapping subcellular organization through organelle immunocapture coupled with mass spectrometry, revealing the dynamic remodeling of human proteins across cellular states (ref: Hein doi.org/10.1016/j.cell.2024.11.028/). This foundational work sets the stage for further exploration of gene editing applications in cellular biology. In the realm of psychiatric disorders, Lee et al. utilized a massively parallel reporter assay to investigate shared genetic variants across eight disorders, demonstrating that pleiotropic variants exhibit chromatin accessibility across diverse neuronal cell types, which may influence gene regulation (ref: Lee doi.org/10.1016/j.cell.2024.12.022/). This highlights the potential of gene editing to unravel complex genetic interactions in neurobiology. Moreover, Zhang et al. presented a multiplex universal combinatorial immunotherapy approach using CRISPR-Cas13d to silence multiple immunosuppressive genes in the tumor microenvironment, significantly enhancing antitumor immunity in various syngeneic tumor models (ref: Zhang doi.org/10.1038/s41587-024-02535-2/). This innovative application of gene editing not only demonstrates its therapeutic potential in cancer treatment but also emphasizes the importance of targeting multiple pathways simultaneously. Additionally, studies on base editing by Muller et al. and An et al. showcased high-efficiency editing techniques in human retinal tissues and mouse models of prion disease, respectively, further illustrating the versatility and precision of modern gene editing technologies (ref: Muller doi.org/10.1038/s41591-024-03422-8/; ref: An doi.org/10.1038/s41591-024-03466-w/). Overall, these studies collectively underscore the transformative impact of gene editing techniques in both basic research and therapeutic applications.

The intersection of cancer immunotherapy and gene editing has emerged as a promising frontier in cancer treatment, with several studies demonstrating innovative strategies to enhance therapeutic efficacy. Zhang et al. introduced a multiplex universal combinatorial immunotherapy approach using CRISPR-Cas13d to silence immunosuppressive genes within the tumor microenvironment, resulting in significant antitumor effects across multiple syngeneic tumor models (ref: Zhang doi.org/10.1038/s41587-024-02535-2/). This study highlights the potential of gene editing to remodel the tumor microenvironment and improve immune responses against tumors. Furthermore, An et al. explored in vivo base editing strategies to modify the PRNP locus in a mouse model of prion disease, showcasing the versatility of gene editing techniques in addressing various diseases, including cancer (ref: An doi.org/10.1038/s41591-024-03466-w/). In addition, Jadlowsky et al. conducted a comprehensive evaluation of the long-term safety of lentiviral and gammaretroviral gene-modified T cell therapies, analyzing data from 783 patients over 2,200 patient-years. Their findings provide critical insights into the safety profiles of these therapies, which are essential for their application in cancer treatment (ref: Jadlowsky doi.org/10.1038/s41591-024-03478-6/). The integration of gene editing technologies into immunotherapy frameworks not only enhances the specificity of treatments but also addresses the challenges posed by tumor heterogeneity and immune evasion. Collectively, these studies illustrate the transformative potential of combining gene editing with immunotherapeutic strategies to improve cancer treatment outcomes.

Innovations in CRISPR technology and genome engineering have paved the way for groundbreaking applications in various fields, including cancer research and genetic disease modeling. Koeppel et al. introduced a novel approach utilizing CRISPR prime editing to engineer recombination handles in repetitive sequences, enabling large-scale genomic rearrangements and enhancing our ability to study noncoding regions of the human genome (ref: Koeppel doi.org/10.1126/science.ado3979/). This advancement addresses a significant gap in our ability to manipulate vast portions of the genome that were previously inaccessible, thereby expanding the toolkit available for genetic research. Additionally, Jonsdottir et al. developed a scalable CRISPR-Cas9 system for high-throughput gene editing in the malaria parasite Plasmodium berghei, which allows for more comprehensive genetic studies in this organism (ref: Jonsdottir doi.org/10.1093/nar/). This system enhances genetic tractability and facilitates large-scale knockout screens, which are crucial for understanding gene function in malaria. Furthermore, Garcia-Guerra et al. explored tissue-specific modulation of CRISPR activity using miRNA-sensing guide RNAs, offering a promising strategy to enhance the precision of gene editing while minimizing off-target effects (ref: Garcia-Guerra doi.org/10.1093/nar/). These innovations collectively underscore the rapid evolution of CRISPR technologies and their potential to revolutionize genetic research and therapeutic applications.

The exploration of genetic variants and their implications in disease mechanisms has gained momentum, particularly with the advent of advanced genomic technologies. Lee et al. conducted a massively parallel reporter assay to investigate the regulatory logic of genetic variants associated with eight psychiatric disorders, revealing that pleiotropic variants exhibit chromatin accessibility across diverse neuronal cell types, which may influence gene expression and contribute to disease susceptibility (ref: Lee doi.org/10.1016/j.cell.2024.12.022/). This study emphasizes the complexity of genetic interactions and the need for comprehensive approaches to understand the genetic basis of psychiatric conditions. In parallel, Funk et al. performed a deep mutational scan of the TP53 gene, a critical tumor suppressor, to characterize the functional diversity of over 9,000 TP53 variants in cancer cells (ref: Funk doi.org/10.1038/s41588-024-02039-4/). Their findings provide valuable insights into how specific mutations can influence cancer progression and treatment responses, highlighting the importance of personalized medicine approaches. Additionally, the study by Liu et al. on engineered neutrophil nanovesicles for corneal neovascularization therapy underscores the multifaceted nature of genetic regulation in disease processes, as it combines genetic engineering with therapeutic delivery systems to address complex pathological conditions (ref: Liu doi.org/10.1002/adma.202411030/). Collectively, these studies illustrate the intricate relationship between genetic variants and disease mechanisms, underscoring the potential for targeted interventions based on genetic insights.

Base editing has emerged as a powerful tool for precise genetic modifications, with significant implications for therapeutic applications. Muller et al. optimized base editing techniques for the ABCA4 gene in human retinal tissues, demonstrating high efficiency and specificity in correcting mutations associated with Stargardt disease, a leading cause of inherited blindness (ref: Muller doi.org/10.1038/s41591-024-03422-8/). Their work highlights the potential of base editing to provide effective treatments for genetic disorders that currently lack viable therapies. Similarly, An et al. developed in vivo base editing strategies to target the PRNP locus in a mouse model of prion disease, showcasing the ability to achieve significant gene knockdown and extend lifespan in affected mice (ref: An doi.org/10.1038/s41591-024-03466-w/). This study not only demonstrates the therapeutic potential of base editing in neurodegenerative diseases but also emphasizes the importance of precise genetic modifications in developing effective treatments. Furthermore, the long-term safety evaluation of lentiviral and gammaretroviral gene-modified T cell therapies by Jadlowsky et al. provides critical insights into the safety profiles of these approaches, which are essential for their application in cancer immunotherapy (ref: Jadlowsky doi.org/10.1038/s41591-024-03478-6/). Together, these studies illustrate the transformative potential of base editing technologies in addressing a wide range of genetic disorders and enhancing therapeutic outcomes.

Understanding gene regulation and expression control is crucial for elucidating the mechanisms underlying cellular function and disease. Fan et al. investigated the role of the Integrator-PP2A complex (INTAC) in mediating sensitivity to BET inhibitors, revealing that the efficacy of these inhibitors in cancer therapy is influenced by the auxiliary module of INTAC (ref: Fan doi.org/10.1038/s41589-024-01807-x/). This study highlights the intricate regulatory networks that govern gene expression and their implications for therapeutic interventions in cancer. Additionally, Zhang et al. reported on a trigger-inducible split-Csy4 architecture for programmable RNA modulation, which offers a novel approach to control transgene expression while minimizing off-target effects (ref: Zhang doi.org/10.1093/nar/). This innovative system enhances the precision of gene regulation, making it a valuable tool for therapeutic applications. Furthermore, Jungfer et al. explored the dynamics of cyclic oligoadenylate synthesis in type III CRISPR-Cas systems, shedding light on the mechanisms by which these systems reinforce host immune responses (ref: Jungfer doi.org/10.1093/nar/). Collectively, these studies underscore the importance of understanding gene regulation and expression control in developing effective therapeutic strategies and advancing our knowledge of cellular biology.

The development of CRISPR technology has revolutionized the field of genetic engineering, enabling precise modifications and novel applications across various organisms. Jonsdottir et al. introduced a scalable CRISPR-Cas9 system designed for high-throughput gene editing in the malaria parasite Plasmodium berghei, which allows for comprehensive genetic studies and enhances the tractability of this organism for research purposes (ref: Jonsdottir doi.org/10.1093/nar/). This advancement is crucial for understanding the genetic basis of malaria and developing targeted interventions. Moreover, Garcia-Guerra et al. explored the use of miRNA-sensing guide RNAs to achieve tissue-specific modulation of CRISPR activity, presenting a promising strategy to enhance the specificity of gene editing while reducing off-target effects (ref: Garcia-Guerra doi.org/10.1093/nar/). This innovation addresses a significant challenge in CRISPR applications, making it more applicable for therapeutic uses. Additionally, Chen et al. developed a macrophage-specific editing system that enables RNA editing in vivo, demonstrating the potential of CRISPR technologies to target specific cell types for therapeutic purposes (ref: Chen doi.org/10.1126/scitranslmed.adl5800/). Together, these studies highlight the rapid advancements in CRISPR technology and its potential to transform genetic research and therapeutic applications.

Investigating the molecular mechanisms underlying cancer is essential for developing effective therapeutic strategies. Funk et al. conducted a deep CRISPR mutagenesis study to characterize the functional diversity of TP53 mutations, a critical tumor suppressor gene frequently altered in various cancers (ref: Funk doi.org/10.1038/s41588-024-02039-4/). Their findings reveal the complex interplay between specific mutations and cancer progression, providing insights that could inform personalized treatment approaches. In addition, Liu et al. developed engineered neutrophil nanovesicles for inhibiting corneal neovascularization, demonstrating a novel approach to address pathological conditions associated with cancer (ref: Liu doi.org/10.1002/adma.202411030/). This study highlights the potential of combining genetic engineering with therapeutic delivery systems to target cancer-related processes. Furthermore, Zhang et al. introduced a trigger-inducible split-Csy4 architecture for programmable RNA modulation, which could enhance the specificity of gene regulation in cancer therapies (ref: Zhang doi.org/10.1093/nar/). Collectively, these studies underscore the importance of understanding molecular mechanisms in cancer and the potential for innovative therapeutic strategies that leverage genetic insights.