Takahiko Murayama

Cancer cells survive, proliferate, and metastasize in part because the immune system fails to detect and eliminate them. Moreover, the tumor microenvironment (TME) that surrounds the tumor supports cancer cell survival and resistance to chemo- and immunotherapies by inhibiting antitumor immune responses and thereby reducing the efficacy of immunotherapeutic interventions. cGAS-STING signaling senses cytoplasmic DNA and coordinates innate immune responses that shape tumor-intrinsic outcomes and the TME. Emerging evidence reveals a context-dependent, dualistic role for cGAS-STING in metastatic progression and cancer dormancy. Acute, robust activation in antigen-presenting cells promotes type I interferon responses, leading to suppression of tumor growth. By contrast, chronic, low-level cancer-intrinsic STING signaling can engage inflammatory programs that foster immune suppression and therapy resistance. Dormant disseminated tumor cells exploit niche cues to downregulate STING signaling and evade immune detection, whereas reactivation of dormant cells often involves restoration of STING activity that can promote immune elimination. In this article, we review mechanisms linking genome instability and cytoplasmic DNA to STING activation, summarize evidence for tumor-suppressive versus tumor-promoting functions across metastatic niches, and discuss how STING agonists and combination strategies may be optimized to maximize antitumor immunity while avoiding protumorigenic effects.

Recurrence and metastasis remain major causes of cancer mortality, sustained by therapy–resistant micrometastatic cells. Bone is a frequent site of breast–cancer relapse, yet the cues that reawaken disseminated cells remain poorly defined. We identify a previously unrecognized, highly plastic CXCL16⁺ macrophage population that integrates tumor–associated macrophage programs found in distant metastatic sites such as lung and brain with non–tumor disease–associated traits in bone marrow. These CXCL16⁺ macrophages establish a transient niche that restrains disseminated cancer–cell proliferation. Single–cell transcriptomics delineate functional remodeling of myeloid niches within the bone metastatic microenvironment: a CXCL16⁺ macrophage niche that transiently constrains metastatic growth, and G–CSF⁺ macrophage and neutrophil niches that reignite tumor outgrowth. In primary tumors, cancer–associated fibroblasts (CAFs) aberrantly secrete G–CSF in response to cancer–cell signals, expanding G–CSF–receptor–positive subset of cancer cells with high metastatic potential. In advanced human bone metastases, CXCL16⁺ macrophages localize to CAF–rich stroma but are excluded from cancer–cell clusters, indicating immune evasion. Together, these findings uncover CAF–bone–marrow cross–talk as a therapeutic target linking stromal inflammation, immune remodeling, and metastatic progression.

The Research Topic entitled "RNA Helicases: Pioneering Therapeutic Avenues in Cancer Treatment" explores the emerging role of RNA helicases as central regulators of fundamental cellular processes whose dysregulation contributes to tumor initiation, progression, and therapeutic resistance. Over the last decade, increasing evidence has highlighted the importance of these enzymes not only in RNA metabolism but also in the maintenance of genome stability, cellular stress responses, and immune regulation, positioning them as attractive targets for cancer therapy.The aim of this Research Topic is to provide new evidence supporting the functional relevance of RNA helicases as cancer-associated regulators while highlighting molecular mechanisms that may be exploited for therapeutic intervention. In addition, the collection discusses emerging strategies to improve treatment efficacy by targeting RNA helicases directly or by exploiting pathways that depend on their activity.Mini-Review articles. Together, these contributions provide a comprehensive overview of the diverse biological functions of RNA helicases, including their roles in RNA processing, resolution, cellular 37 stress responses, and transcriptional regulation. Collectively, the articles emphasize the 38 remarkable functional versatility of this protein family and its growing relevance in cancer biology. 39 We anticipate that this collection will be of interest to a broad readership, including basic 86 researchers, translational scientists, and clinicians working in oncology and RNA biology. Nevertheless, 87 these articles address only a fraction of the many unresolved questions surrounding the diverse and context-88 dependent functions of RNA helicases. Further investigations will be essential to elucidate the molecular 89 mechanisms governing helicase activity, identify predictive biomarkers of response, and develop more 90 selective and effective therapeutic strategies with reduced toxicity. Continued research in this rapidly 91 evolving field is expected to uncover new opportunities for targeting RNA helicases and their associated 92 pathways in cancer treatment. 93

RNA helicases are enzymes that remodel RNA secondary structures and RNA-protein complexes using ATP-driven motor forces. They are known to participate in many essential cellular processes, including transcription, splicing, translation, RNA decay, and ribosome assembly. However, the functional diversity of RNA helicases and the multitude of associated cofactors make it difficult to grasp the full picture of their roles in these processes. Here, we focus exclusively on the R-loop-unwinding activities of RNA helicases and the cofactors involved in this process. R-loops are three-stranded nucleic acid structures that are mainly formed during transcription between newly synthesized mRNA and its template DNA. Timely resolution of R-loops by RNA helicases is required to prevent the DNA damage and replication stress that can result from collisions between transcription and DNA replication machinery acting aberrantly on the same DNA strand. Although R-loop resolution is critical for genome stability and cell proliferation, our understanding of the responsible helicases and their mechanisms remains incomplete. In this review, we summarize recent findings on R-loop-resolving helicases, discuss key questions and approaches for future investigation, and consider the potential of targeting these helicases for cancer therapy.

Figure S1 shows TREX1 expression is induced in drug resistant SCLC cells

Drug transporter expression levels in H69AR vs H69

Figure S2 shows TREX1 loss suppresses SCLC growth and induces immune response

Figure S3 shows immunogenicity is induced in TREX1 depleted cells

Figure S5 shows TREX1 expression is induced in post-treated SCLC PDX

Table S1 from Targeting TREX1 Induces Innate Immune Response in Drug-Resistant Small-Cell Lung Cancer