Written by丨YiSmall cell lung cancer (SCLC) is a typical cold tumor and is the deadliest subtype of lung cancer. Due to its close association with smoking, SCLC is one of the tumors with the highest mutational burden, characterized by decreased antigen presentation and an immune desert (TME) of the tumor microenvironment. Although first-line** immune checkpoint blockade (ICB) is added to standard platinum-based chemotherapy**, only a minority of patients with SCLC have a lasting benefit from these**. Therefore, there is an urgent need to identify new ** targets that can enhance anti-tumor immunity and enable these cold tumors to be sensitive to ICB**. Activating innate immunity in tumor cells is an effective way to enable cold tumors to turn into hot tumors, thereby enhancing the response to ICB**. Inducing intracellular accumulation of endogenous "viral mimetic nucleic acids", including double-stranded RNA and double-stranded DNA, is a promising strategy to trigger innate immune responses within tumors and promote tumor immunity**. These nucleic acids are perceived by the host innate immune system as evidence of viral replication and elicit an IFN-driven antiviral response. This antiviral response is highly immunogenic and has shown very promising results in several preclinical models and clinical trials. Recently, Philadelphia Cancer Hospital, USAisrael canadasThe team is incancer discoveryPublished in the journal entitled:targeting dhx9 triggers tumor-intrinsic interferon response and replication stress in small cell lung cancerResearch**,DexD H-box helicase 9 was identified by CRISPR-based RNA helicase screening（dhx9）is double-stranded RNA in SCLC（dsrna）Potent inhibitors。Knockdown of DHX9 induces cytoplasmic dsRNA accumulation and triggers innate immunity in tumor cells. Knockdown of DHX9 also induced abnormal accumulation of r-loops, leading to increased DNA damage and DNA replication stress. In vivo experiments in miceDeletion of DHX9 inhibited tumor growth while inducing an immunogenic tumor microenvironment and enhancing the response to ICB**。This study describes for the first time the role of DHX9 in tumor immunity and genomic instability, identifying a novel viral mimetic induction strategy to enhance anti-tumor immunity and promote cold tumor immunity**. 
Studies have shown that some RNA helicases have the ability to unwind DSRNA structures. Therefore, the authors hypothesize that targeting RNA helicases will be a novel strategy to induce innate immune responses by accumulating dsRNA in cold tumors. The authors first measured DSRNA levels in SCLC cells with sgRNA treatment targeting 32 RNA helicases in the H446 SCLC cell line, based on flow cytometry-based CRISPR screening. As a result, a rich RNA helicase was discovered, dexD H-box helicase 9 (DHX9), and the knockout of DHX9 significantly increased the level of DSRNA, and the tumor cell type with the highest DHX9 expression level was also found in the Cancer Cell Line Encyclopedia (CCLE) database was the SCLC cell line. Consistent with this, SCLC also showed the highest levels of DHX9 expression among all lung cancer subtypes. These results suggest that DHX9 may be a promising target for **SCLC. To further investigate the biological effects of dsRNA accumulation in SCLC cells, the authors performed RNA-Seq on SGDHX9 SCLC cells. GSA9 analysis showed that DHX9 knockdown induced upregulation of gene expression pathways related to immune and inflammatory responses and cytokine activity, with increased expression of many interferon-stimulated genes (ISGS). Q-PCR also verified that DHX9 deletion strongly induced the expression of multiple ISGS (IFNb, CXCL10, CXCL11, CCL2) and NF-B response genes (INFA, IL1B, RELB). In addition, the increase in the levels of P-IRF3 and P-TBK1, the increase in IFN- secretion in the culture medium, and the up-regulation of the expression of HLA-A, B, C, and PD-L1 on the surface of SCLC cells were also detected, indicating that DHX9 deletion activated the DSRNA-sensing pathway, initiated the antiviral transcription program, induced the IFN response in SCLC cells, and activated the anti-tumor immune pathway in SCLC cells. In addition, the authors also found that DHX9 deletion leads to R-loop accumulation, triggers replication stress, causes DNA damage, and leads to genomic instability. Through a series of in vivo experiments, the authors determined that knockdown of DHX9 reduced tumor growth, induced immune cell infiltration, and enhanced the response to ICB**, improving ICB** outcomes. 
Schematic diagram of inhibition of DHX9 to enhance anti-tumor immunity In summary, this study found that DHX9 is an important inhibitor of DSRNA and R loop accumulation, and knockdown of DHX9 can lead to the activation of innate immune responses of tumor cells, as well as DNA replication stress and DNA damage, these properties can transform cold tumors into hot tumors, significantly enhance the reactivity of ICB, and indicate that DHX9 can be used as a potential new target to promote immunity in cold tumors**. Original link:
2024 Travel Guide