Alterations in the tumor microenvironment are closely associated with the metabolic phenotype of tumor cells. Cancer-associated fibroblasts (CAFs) play a pivotal role in tumor growth and metastasis. Existing studies have suggested that lactate produced by tumor cells can activate CAFs, yet the precise underlying mechanisms remain largely unexplored. In this study, we initially identified that lactate derived from lung cancer cells can promote nuclear translocation of NUSAP1, subsequently leading to the recruitment of the transcriptional complex JUNB-FRA1-FRA2 near the DESMIN promoter and facilitating DESMIN transcriptional activation, thereby promoting CAFs' activation. Moreover, DESMIN-positive CAFs, in turn, secrete IL-8, which recruits TAMs or promotes M2 polarization of macrophages, further contributing to the alterations in the tumor microenvironment and facilitating lung cancer progression. Furthermore, we observed that the use of IL-8 receptor antagonists, SB225002, or Navarixin, significantly reduced TAM infiltration and enhanced the therapeutic efficacy of anti-PD-1 or anti-PD-L1 treatment. This finding indicates that inhibiting IL-8R activity can attenuate the impact of CAFs on the tumor microenvironment, thus restraining the progression of lung cancer.

Cell lineage plasticity is one of the major causes for the failure of targeted therapies in various cancers. However, the driver and actionable drug targets in promoting cancer cell lineage plasticity are scarcely identified. Here, we found that a G protein-coupled receptor, ADORA2A, is specifically upregulated during neuroendocrine differentiation, a common form of lineage plasticity in prostate cancer and lung cancer following targeted therapies. Activation of the ADORA2A signaling rewires the proline metabolism via an ERK/MYC/PYCR cascade. Increased proline synthesis promotes deacetylases SIRT6/7-mediated deacetylation of histone H3 at lysine 27 (H3K27), and thereby biases a global transcriptional output toward a neuroendocrine lineage profile. Ablation of Adora2a in genetically engineered mouse models inhibits the development and progression of neuroendocrine prostate and lung cancers, and, intriguingly, prevents the adenocarcinoma-to-neuroendocrine phenotypic transition. Importantly, pharmacological blockade of ADORA2A profoundly represses neuroendocrine prostate and lung cancer growth in vivo. Therefore, we believe that ADORA2A can be used as a promising therapeutic target to govern the epigenetic reprogramming in neuroendocrine malignancies.

TGFβ1 signaling is a critical driver of collagen accumulation in pulmonary fibrotic diseases and a well-characterized regulator of cancer associated fibroblasts (CAF) activation in lung cancer. Myofibroblasts induced by TGFβ1 and other factors are key players in the pathogenesis of lung fibrosis and tumor. Tremendous attention has been gained to targeting myofibroblasts in order to inhibit the progression of fibrosis and myofibroblast-induced tumor progression and metastasis. Here we determined the therapeutic efficacy of simultaneously targeting PI3K and HDAC pathways in lung myofibroblasts and CAF with a single agent and to evaluate biomarkers of treatment response. CUDC-907 is a first-in-class compound, functioning as a dual inhibitor of HDACs and PI3K/AKT pathway. We investigated its effects in counteracting the activity of TGFβ1-induced myofibroblasts/CAF in regard to cell proliferation, migration, invasion, apoptosis in vitro antifibrosis efficiency in vivo. We found that CUDC-907 inhibited myofibroblasts/CAF cell proliferation, migration and apoptosis in a dose-dependent manner and caused cell cycle arrest at G1-S phase. CUDC-907 not only inhibited myofibroblasts markers expression, but also significantly inhibited the phosphorylation level of AKT, mTOR, Smad2/3, and promoted acetylation of histones. Furthermore, the observed inhibitory effect was also confirmed in bleomycin-induced mice lung fibrosis and nude mouse transplanted tumor model. Overall, these data suggest that dual inhibition of HDAC and the tyrosine kinase signaling pathways with CUDC-907 is a promising treatment strategy for TGFβ1-induced lung and tumor fibrosis.

Background: Recently, PANoptosis has aroused the interest of researchers for its role in cancers. However, the studies that investigated PANoptosis in lung cancer are still few.Methods: The public data were mainly collected from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus database. R software was utilized for the analysis of public data. Quantitative real-time (qRT) polymerase chain reaction (PCR) was used to measure the RNA level of FADD. The cell proliferation ability was evaluated using the CCK8, colony formation, and 5-ethynyl-2′-deoxyuridine (EdU) assays. Western blot was used to detect the protein level of specific molecules. Flow cytometry analysis and TUNEL staining were used to evaluate cell apoptosis.Results: In our study, we collected the PANoptosis-related genes from previous studies. Through series analysis, we identified the FADD, an adaptor of PANoptosis and apoptosis, for further analysis. Results showed that FADD is one of the prominent risk factors in lung cancer, mainly localized in nucleoplasm and cytosol. We next performed immune infiltration analysis and biological enrichment to illustrate the underlying cause of FADD in lung cancer. Subsequently, we discovered that the patients with a high level of FADD might respond worse to immunotherapy but better to AICAR, bortezomib, docetaxel, and gemcitabine. In vitro experiments indicated that inhibiting FADD could reduce significantly the ability of cancerous lung cells to proliferate. Meanwhile, we found that the knockdown of FADD promotes the apoptosis and pyroptosis. Ultimately, a prognosis signature was identified based on the FADD-regulated genes, which showed satisfactory prediction efficiency on patients with lung cancer.Conclusion: Our result can provide a novel direction for future studies focused on the role of PANoptosis in lung cancer.

This study aims to investigate the role of RGS2 in immune regulation in lung cancer (LC) and explore the regulatory relationship between RGS2 and BATF2 in modulating T cell exhaustion and tumor immune evasion. Single-cell transcriptome-based analysis was performed to identify CD8+ T-cell profiles and regulatory factors in six LC patients receiving neoadjuvant PD-1 blockade therapy. Mouse 3LL cells or murine tumor organoid models were transplanted into wild-type, RGS2 knock-out (RGS2−/−), or BATF2 knock-out (BATF2−/−) mice to analyze the effects of RGS2 and BATF2 on tumor growth, metastasis, and immune cell infiltration. CD8+ from these mice were isolated and co-cultured with cancer cells to analyze T cell cytotoxicity in vitro. The transcriptional regulation of RGS2 by BATF2 was analyzed using luciferase reporter assays. RGS2 was highly expressed in CD8+ T-exhausted (Tex) cells and was associated with pro-inflammatory pathways. High RGS2 expression predicted poor clinical outcomes and limited response to PD-1/PD-L1 blockade therapy. In RGS2−/− mice, tumor metastasis and angiogenesis were suppressed, CD8+ effector T cells were enhanced, and T cell exhaustion markers were reduced. BATF2 was identified as a key transcriptional regulator of RGS2, promoting T cell exhaustion through inhibition of CXCL13 secretion. Knockdown of BATF2 or RGS2 impaired lung cancer cell proliferation and enhanced sensitivity to NK cell-mediated cytotoxicity in vitro. In BATF2−/− mice, the populations of immune active CD8+ T cells were increased, while exhausted T cells were reduced, leading to improved anti-tumor immune responses. RGS2, regulated by BATF2, plays a critical role in driving T cell exhaustion and tumor immune evasion in LC. Targeting the BATF2-RGS2 axis may enhance the effectiveness of immunotherapy by reversing T cell exhaustion and improving anti-tumor immunity.