Cytosolic double-stranded DNA surveillance by cyclic GMP-AMP synthase (cGAS)–Stimulator of Interferon Genes (STING) signaling triggers cellular senescence, autophagy, biased mRNA translation, and interferon-mediated immune responses. However, detailed mechanisms and physiological relevance of STING-induced senescence are not fully understood. Here, we unexpectedly found that interferon regulatory factor 3 (IRF3), activated during innate DNA sensing, forms substantial endogenous complexes in the nucleus with retinoblastoma (RB), a key cell cycle regulator. The IRF3-RB interaction attenuates cyclin-dependent kinase 4/6 (CDK4/6)–mediated RB hyperphosphorylation that mobilizes RB to deactivate E2 family (E2F) transcription factors, thereby driving cells into senescence. STING-IRF3-RB signaling plays a notable role in hepatic stellate cells (HSCs) within various murine models, pushing activated HSCs toward senescence. Accordingly, IRF3 global knockout or conditional deletion in HSCs aggravated liver fibrosis, a process mitigated by the CDK4/6 inhibitor. These findings underscore a straightforward yet vital mechanism of cGAS-STING signaling in inducing cellular senescence and unveil its unexpected biology in limiting liver fibrosis.

The Hippo/yes-associated protein (YAP) signaling is an evolutionarily conserved regulator in organ size control, which plays pivotal roles in cell proliferation, differentiation, apoptosis, and tissue regeneration. In cancer, dysregulation of Hippo/YAP signaling is typically recognized as one of the crucial drivers in tumorigenesis. However, beyond its canonical transcriptional targets, Hippo/YAP signaling engages in extensive crosstalk with multiple pathways to form an intricate regulatory network, thereby giving rise to its content-dependent influence on tumor initiation, progression and metastasis. This review focuses on the molecular mechanisms underlying the interplay between Hippo/YAP and pivotal signaling pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), wingless-type (Wnt)/β-catenin signaling pathway, transforming growth factor-beta (TGF-β), Hedgehog, Notch and other signaling pathways, as well as their implications in cancer biology. Ultimately, exploiting these mechanisms may represent promising therapeutic strategies for cancer.

Mechanical control is fundamental for cellular localization within a tissue, including for tumor-associated macrophages (TAMs). While the innate immune sensing pathways cGAS-STING and RLR-MAVS impact the pathogenesis and therapeutics of malignant diseases, their effects on cell residency and motility remain incompletely understood. Here, we uncovered that TBK1 kinase, activated by cGAS-STING or RLR-MAVS signaling in macrophages, directly phosphorylates and mobilizes Zyxin, a key regulator of actin dynamics. Under pathological conditions and in STING or MAVS signalosomes, TBK1-mediated Zyxin phosphorylation at S143 facilitates rapid recruitment of phospho-Zyxin to focal adhesions, leading to subsequent F-actin reorganization and reduced macrophage migration. Intratumoral STING-TBK1-Zyxin signaling was evident in TAMs and critical in antitumor immunity. Furthermore, myeloid-specific or global disruption of this signaling decreased the population of CD11b ⁺ F4/80 ⁺ TAMs and promoted PD-1-mediated antitumor immunotherapy. Thus, our findings identify a new biological function of innate immune sensing pathways by regulating macrophage tissue localization, thus providing insights into context-dependent mitigation of antitumor immunity.

Viral latency is a sophisticated survival strategy that allows the viral genome to persist indefinitely while remaining invisible to immune surveillance. This stealth impedes eradication, and episodic reactivation compounds the hurdle, necessitating therapeutic innovation. Recently, increasing evidence has indicated that the cGAS-STING pathway, which senses nonself or damaged DNA, plays vital roles in the establishment, maintenance, and reversal of latency in a subset of viruses. Given its central role in triggering innate immune responses, the cGAS-STING pathway has emerged as a high-priority target for therapeutic intervention. Here, we outline the multilayered arms race between latent viruses and the cGAS-STING pathway. Latent viruses generally conceal their genomes from cGAS, disrupt cGAS-STING signaling to limit innate immune responses, and subsequently deploy latency-associated factors to maintain pathway silencing and evade immune surveillance. We also elucidated the paradoxical engagement of cGAS-STING during reactivation. Motivated by encouraging preclinical data on STING agonists and the central role of the STING signaling pathway in cell fate decisions, we synthesized the current knowledge and proposed targeting this pathway for therapeutic intervention to reduce viral latency.

Intratumoral glucose availability is linked considerably to tumor growth, immune evasion, and metastasis. However, the precise molecular mechanisms by which glucose levels govern cellular and immune responses against tumors remain incompletely understood. Here, we explored the context of tumors of intersections between AMP-activated protein kinase (AMPK) and cGAS-STING signaling, a key pathway initiating antitumor immunity. We unexpectedly found that AMPK activation robustly enhances cGAS-STING signaling within cancer and immune cells, which potently impacts melanoma and colorectal cell senescence, organoid apoptosis, and the infiltration of CD4 ⁺ and CD8 ⁺ T lymphocytes. Using classic or newly developed AMPK agonist Aldometanib, TBK1 ^S511E/S511E knock-in (KI) mice, glucose metabolic modulator, as well as AMPKα1/α2 dKO melanoma, we demonstrated that dual sensing of intratumoral glucose and dsDNA integrated by the AMPK-TBK1 cascade is essential for initiating antitumor immunity and suppressing cancer progressions. Notably, novel AMPK agonists or intervening in glucose glycolysis by Lonidamine synergized effectively with STING agonists, substantially inhibiting melanoma growth. Therefore, these findings unravel a concise mechanism integrating glucose metabolism and innate DNA sensing into cancer cell fate and propose an effective therapeutic strategy to enhance antitumor immunity. HIGHLIGHTS: Dual and synergistic sensing of glucose and dsDNA facilitates antitumor immunity in melanoma and colorectal cancer; AMPK substitutes intratumoral cGAS-STING-IRF3 signaling through TBK1 phosphorylation at S511; Glucose deficiency induces cancer cell senescence, apoptosis, and T lymphocyte infiltration via the AMPK-TBK1 cascade; Newly developed AMPK agonists synergize with STING agonists to retrieve striking tumor suppression.