From RNAi to single-cell CRISPR: Evolving functional screening in aging and cancer

Interconnected roles of cellular senescence and the immune microenvironment in tumor progression: from pan-cancer mechanisms to glioblastoma implications

Cellular senescence is an irreversible cell state induced by diverse stressors, characterized by permanent cell cycle arrest coupled with sustained metabolic activity. In the context of tumor evolution, senescence exhibits remarkable complexity and dynamism: it functions not only as an early tumor-suppressive barrier that blocks malignant transformation but also recruits and reprograms immune cells through the senescence-associated secretory phenotype (SASP), thereby constructing a distinctive tumor microenvironment (TME). Concurrently, the status of the immune system, including the efficacy of immunosurveillance and the occurrence of local immune exhaustion, reciprocally determines the ultimate fate of senescent cells and governs the transition between their tumor-suppressive and tumor-promoting effects. This dynamic tripartite regulatory network comprising senescence, immunity, and the tumor constitutes the core framework for understanding tumor heterogeneity and drug resistance mechanisms. Advances in single-cell and spatial multi-omics technologies have provided unprecedented precision for dissecting the spatiotemporal evolution of this network. Current efforts to integrate senescence-targeted interventions, such as combinatorial “induce-modulate-eliminate” strategies, with modern immunotherapy show immense potential, although precisely breaching physical barriers and eradicating highly invasive senescent clones remain formidable challenges. This review systematically examines the molecular mechanisms of cellular senescence, with emphasis on the intrinsic logic governing bidirectional remodeling between senescent cells and the immune microenvironment. Glioblastoma (GBM) serves as the focal disease model throughout, providing in-depth analysis of how these mechanisms manifest within a highly immune-privileged ecosystem and their therapeutic implications. By dissecting the interplay between pan-cancer mechanisms and the GBM-specific microenvironment, this review aims to provide a new theoretical foundation for next-generation precision cancer immunotherapy.

Epigenome-Wide CRISPR-Cas9-Based Knockout Screens on Chemoresistant Cells.

Key methodological steps for achieving high-efficiency lentiviral transduction and selection are described, enabling the successful application of EPIKOL CRISPR screens in chemoresistant TNBC models.

Genomic, epigenomic and transcriptomic regulation of cellular senescence.

Context-dependent cancer vulnerabilities: CRISPR screening under inflammatory stress.

Genome-wide CRISPR screens have systematically identified genes required for cancer cell survival, yet these studies are typically performed under standardized conditions that do not fully recapitulate the physiological stresses encountered within the tumor microenvironment. In a recent issue of Nature Genetics, Cheruiyot and colleagues perform genome-wide loss-of-function screens under inflammatory conditions induced by interferon-β (IFN-β), interferon-γ (IFN-γ), and tumor necrosis factor (TNF), revealing that distinct cytokines impose different genetic requirements for tumor cell survival. The study shows that inflammatory signaling reshapes genetic dependency landscape in a cytokine-specific manner. Mechanistic analyses identify the glycosylphosphatidylinositol (GPI) transamidase complex and FITM2 as representative examples of genes that become selectively required under inflammatory stress by maintaining membrane protein maturation, endoplasmic reticulum homeostasis, and resistance to oxidative stress. These findings broaden our understanding of how inflammatory cytokines influence tumor cell biology beyond transcriptional regulation and immune recognition. More broadly, the study highlights the value of incorporating physiologically relevant conditions into functional genetic screens, suggesting that conventional dependency maps capture only part of the genetic requirements for tumor survival. Applying similar approaches to other microenvironmental stresses-including hypoxia, metabolic competition, extracellular matrix remodeling, and stromal signaling-may uncover additional therapeutic opportunities for cancer immunotherapy.

Decoding the tumor-aging axis: from bench to clinical

Population aging is a major global health challenge and a principal risk factor for cancer. Aging does not simply increase mutational burden; it reshapes tissue homeostasis across genetic, epigenetic, metabolic, immune, and systemic dimensions. Genomic instability, epigenetic drift, mitochondrial dysfunction, and metabolic rewiring collectively establish a tumor-permissive landscape that enhances clonal diversification and lowers the threshold for malignant transformation. Concurrently, accumulation of senescent cells and the senescence-associated secretory phenotype (SASP) remodel the microenvironment, promote immune suppression, and weaken tumor surveillance, further exacerbated by immunosenescence and gut microbiota dysbiosis. Importantly, cancer progression feeds back to accelerate organismal aging. Tumor burden and therapy-induced stress destabilize hematopoietic and non-hematopoietic stem cell niches, disrupt systemic metabolic homeostasis, and induce neuroendocrine reprogramming, thereby amplifying multi-organ functional decline. Aging and cancer therefore constitute a bidirectional and self-reinforcing network rather than a linear cause-effect relationship. In this review, we synthesize mechanistic, clinical, and translational evidence defining the tumor-aging axis and discuss emerging strategies aimed at interrupting this pathogenic cycle.

Epigenetic reprogramming of lineage switching in cancer.

This review evaluating how the antagonistic interplay between Polycomb and Trithorax complexes, chromatin modifier activity, and enhancer reprogramming affects lineage identity and enables multi-lineage plasticity in cancer underscores epigenetic deregulation as a primary driver of lineage plasticity and intratumoral heterogeneity.