Targeting the DNA damage response to reshape the tumor immune microenvironment

The DNA damage response and cancer immunotherapy

The cGAS/STING pathway in cancer: translating innate DNA sensing into therapeutic potential

How context determines the consequences of cGAS/STING activation in cancer is examined, emerging therapeutic strategies that modulate this pathway are reviewed, and how its antitumor potential can be maximized while minimizing systemic toxicity and immune dysregulation is discussed.

DNA Repair, Epigenetic Dysregulation, and Cytokine Network Crosstalk in Head and Neck Cancer: Emerging Therapeutic Opportunities and Clinical Trials

Exploiting DNA damage tolerance for precision oncology.

Unresolved DNA lesions trigger replication stress, forcing cancer cells to hijack DNA damage tolerance (DDT) networks, specifically translesion synthesis (TLS) and template switching, to sustain replication. While DDT prevents lethal fork collapse, error-prone TLS drives mutagenesis, tumor evolution, chemoresistance and radioresistance. Proliferating cell nuclear antigen post-translational modifications dynamically govern pathway selection. Cancer cells exploit this plasticity, creating actionable vulnerabilities such as postreplicative single-stranded DNA gaps. Emerging inhibitors targeting TLS polymerases, upstream regulators such as ubiquitin-specific peptidase 1 (USP1), and critical protein-protein interactions offer unprecedented opportunities for precision oncology. By integrating DDT inhibition with biomarkers such as homologous recombination deficiency and tumor mutational burden, we can drive synthetic lethality, sensitize tumors to genotoxic agents, suppress treatment-induced mutagenesis, and potentially enhance responses to immunotherapy.

Targeting E3 ubiquitin ligases: Mechanistic breakthroughs and novel clinical translation pathways for tumor radioimmunotherapy

The combination of radiation therapy and immunotherapy has become a cornerstone of modern clinical cancer treatment. However, the inherent radiation resistance of tumors and complex immune evasion mechanisms remain major bottlenecks limiting their long-term effects and sustained efficacy. E3 ubiquitin ligases critically influence tumor sensitivity to radioimmunotherapy by controlling protein stability across DNA repair, immune signaling, and stress-response pathways. This review systematically dissects the multidimensional molecular network through which E3 ubiquitin ligases regulate radiosensitivity and immunoresponsiveness. At the intracellular level, we provide an in-depth analysis of how E3 ubiquitin ligases determine the fate of radiation-induced damage repair by precisely regulating the kinetics of the DNA damage response (DDR), cell cycle checkpoints, and apoptosis thresholds. At the extracellular level, this study focuses on the key roles of E3 ubiquitin ligases in reshaping the immune microenvironment, including the maintenance of spatiotemporal stability of immune checkpoints, the fidelity of antigen processing and presentation, and the epigenetic regulation of microenvironmental dynamic plasticity. Recent studies indicate that E3 ubiquitin ligases link radiation-induced DDR signaling to innate and adaptive immune activation, particularly through the induction of immunogenic cell death (ICD) and the calibration of innate immune sensing pathways like cGAS-STING. Finally, we provide a comprehensive synthesis of cutting-edge translational strategies targeting E3 ubiquitin ligases—ranging from canonical inhibitors to transformative proteolysis-targeting chimeras (PROTACs) and molecular glue degraders (MGDs)—offering novel paradigms for overcoming therapeutic resistance and refining personalized radioimmunotherapy.

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.