Cancer Communications最新文献

Background: Lung cancer remains a major global health burden. RNA-binding proteins (RBPs) play crucial roles in post-transcriptional gene regulation, and their dysregulation is frequently implicated in tumorigenesis. The present study aimed to elucidate the molecular network governed by the highly expressed RBP TIMELESS in lung adenocarcinoma (LUAD) and determine its mechanistic role in LUAD progression. Methods: The Cancer Genome Atlas-LUAD, Gene Expression Omnibus, and single-cell RNA sequencing datasets were analyzed to identify aberrantly expressed RBP genes. The RBP gene TIMELESS exhibited the most significant effect on LUAD cell death and was selected for further study. Photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation sequencing and RNA sequencing were employed to identify ferroptosis-related targets directly bound by TIMELESS. Molecular mechanisms underlying the TIMELESS-mediated regulation of ferroptosis in LUAD were investigated via immunoprecipitation-mass spectrometry, glutathione S-transferase pull-down, immunofluorescence-fluorescence in situ hybridization, RNA immunoprecipitation, poly(A)-tail, and RNA stability assays. In an orthotopic lung cancer mouse model treated with erastin (a ferroptosis inducer) and programmed cell death protein 1 (PD-1) blockade, the role of TIMELESS in therapeutic response was assessed via flow cytometry and multiplex immunofluorescence (mIF). Infiltrating immune cells in LUAD were analyzed by tissue microarrays (TMAs) via mIF. Results: TIMELESS significantly affected LUAD cell proliferation and death, and TIMELESS knockdown significantly enriched RNA-binding and ferroptosis pathways. Transferrin (TF) was identified as a direct TIMELESS target governing ferroptosis. TIMELESS was revealed to bind Ccr4-Not transcription complex subunit 3 (CNOT3) to promote TF mRNA degradation. TIMELESS depletion combined with erastin and PD-1 blockade enhances efficacy, prolongs survival, increases T cell and M1 macrophage infiltration, and reduces M2 macrophage infiltration. Further, high TIMELESS expression was inversely correlated with ferroptosis marker 4-hydroxynonenal but positively correlated with programmed cell death ligand 1 (PD-L1), reduced T cell and M1 macrophage infiltration, and increased M2 macrophage infiltration. Conclusions: TIMELESS recruits CNOT3 to accelerate TF mRNA degradation, thereby suppressing ferroptosis and promoting LUAD growth. These findings suggest that the TIMELESS/TF regulatory axis may be a promising therapeutic target for LUAD.

Cytokines are essential components of the tumor microenvironment (TME) and play crucial roles in tumor initiation and progression. As key mediators of interactions between immune cells and tumor cells within the TME, many cytokines exhibit both protumor and antitumor properties. This complex duality, reminiscent of the balance philosophy pursued by "Onmyoji" in traditional Eastern philosophy, which involves observing and regulating opposing forces to achieve harmony, poses marked challenges in translating cytokine therapies from animal studies to clinical applications. More than 20 key cytokines constituting the TME primarily exert their effects through autocrine and paracrine mechanisms: on one hand, they can activate antitumor immune cells, inhibit tumor growth and metastasis, and induce tumor cell apoptosis to exert antitumor effects; on the other hand, they can also recruit abundant immunosuppressive cells, promote angiogenesis, and facilitate the formation of immunosuppressive microenvironments, thereby preventing natural killer and T cells from exerting their cytotoxic antitumor functions. During acute immune responses triggered by tumor antigens, the body typically stimulates dendritic cell maturation and antigen presentation, leading to antitumor immune responses; however, when acute inflammatory reactions are not promptly resolved, they subsequently transform into chronic inflammation, thereby promoting tumor progression and therapeutic resistance, wherein abundant inflammatory cytokines in the TME play crucial roles in this transition. Currently, the major obstacles to cytokine applications in combination immunotherapy are their poor persistence and uncontrolled toxic side effects, resulting in limited therapeutic efficacy; therefore, reducing toxicity while enhancing efficacy has become a top priority in current cytokine therapy-related research. The effectiveness of cytokines exhibits multifactorial regulation influenced by the unique features of the local TME, cytokine concentration, and the responsiveness profiles of target immune effector cells. This review summarizes current research on cytokines with dual protumor and antitumor effects, with a particular focus on the evolution and regulation of their functions during tumor progression, aiming to provide insights for the future development of personalized immunotherapy strategies targeting cytokines.

Background: Lung metastasis is a leading cause of breast cancer (BC)-related mortality, driven by the immunosuppressive traits of the metastatic tumor microenvironment. However, the mechanisms underlying cell-cell crosstalk in shaping immune evasion within the metastatic niche remain poorly defined. Neutrophil extracellular traps (NETs) and their associated proteins, such as cathelicidin, have emerged as key mediators of metastatic regulation in cancer. Here, we aimed to decipher the interaction between a neutrophil subset characterized by high expression of lymphocyte antigen 6 complex locus g (Ly6g^high) and cluster of differentiation 8-positive T lymphocytes (CD8⁺ T cells), mediated via cathelicidin embedded in NETs, as well as their synergistic mechanism and cooperative role in promoting lung metastasis of BC. Methods: We characterized neutrophil heterogeneity and functional dynamics by performing single-cell RNA sequencing and flow cytometry on lung tissues derived from murine models of BC lung metastasis. We utilized cathelicidin-related antimicrobial peptide (Cramp) knockout mice to dissect the role of cathelicidin in NETs. The spatial colocalization of apoptotic CD8⁺ T cells and NETs was analyzed using multiplex immunofluorescence, and the molecular interactions were probed by protein binding assays. Results: Neutrophils in the lung metastatic niche were classified into 2 subsets based on the Ly6g expression: Ly6g^high and Ly6g^low neutrophils. Ly6g^low neutrophils, which were recruited in the macrometastatic stage, exhibited myeloid-derived suppressor cell-like characteristics. Notably, Ly6g^high neutrophils induced CD8⁺ T cell apoptosis through NET formation, with apoptotic CD8⁺ T cells spatially clustered within NET-rich areas. Mechanistically, NET-derived cathelicidin (Cramp in mice) directly bound to mitochondrial adenine nucleotide translocator 1 (Ant1) in CD8⁺ T cells, triggering conformational changes and complex formation with voltage-dependent anion channel 1 (Vdac1). These events resulted in the opening of the mitochondrial permeability transition pore and loss of mitochondrial membrane potential. Conclusions: Our study demonstrates that Ly6g^high neutrophils play a critical role in immunosuppression and immune evasion through NET-induced apoptosis of CD8⁺ T cells. These findings underscore the importance of NETs and cathelicidin in BC lung metastasis, suggesting their potential as therapeutic targets in restoring antitumor immunity and in preventing metastatic progression.

Background: The prognostic superiority of preoperative chemoradiotherapy (pre-CRT) over preoperative chemotherapy (pre-CT) in patients with locally advanced gastric cancer remains controversial. Herein, we evaluated the efficacy and safety of pre-CRT relative to those of pre-CT in this cohort. Methods: This open-label, phase III, randomized controlled trial was conducted at 4 medical centers in China. Eligible patients with locally advanced gastric cancer or esophagogastric junction adenocarcinoma were randomly assigned (1:1) to receive either 3 cycles of oxaliplatin and S-1 (SOX), followed by surgery and 3 postoperative cycles of SOX (pre-CT), or 1 cycle of SOX, followed by concurrent chemoradiotherapy, a second cycle of SOX, surgery, and 3 postoperative cycles of SOX (pre-CRT). The primary endpoint was 3-year disease-free survival (DFS). Secondary endpoints included 3-year overall survival (OS), R0 resection rate, pathological complete response (pCR) rate, treatment-related toxicity, and postoperative complications. Results: Due to premature trial termination, only 204 patients were enrolled, and an efficacy analysis was conducted on 194 eligible patients. The baseline characteristics were well balanced between the 2 groups. The DFS and OS were indistinguishable between the 2 groups. The 3-year DFS rates were 53.6% in the pre-CRT group and 53.9% in the pre-CT group [hazard ratio (HR), 1.02; 95% confidence interval (CI), 0.70 to 1.50; log-rank P = 0.913]. The 3-year OS rates were 62.8% in the pre-CRT group and 60.5% in the pre-CT group (HR, 0.97; 95% CI, 0.63 to 1.47; log-rank P = 0.874). The R0 resection rates were 81.0% and 74.5% in the pre-CRT and pre-CT groups, respectively. Additionally, the pCR rate was higher in the pre-CRT group (12.0%) than in the pre-CT group (2.1%). Treatment-related toxic effects were comparable between the 2 groups. Conclusion: This trial did not demonstrate a survival advantage for pre-CRT over pre-CT in patients with locally advanced gastric or gastroesophageal adenocarcinoma.

Background: Hypoxia is a prevalent, characteristic feature of the tumor microenvironment (TME) in glioblastomas (GBMs). As dominant immune cells within the TME, glioma-associated macrophages (GAMs) crucially regulate tumor progression. A comprehensive understanding of the effect of hypoxia on the behavior of GAMs is essential for elucidating the immune landscape and developing innovative therapeutic strategies. This study aimed to elucidate the mechanisms by which GAMs facilitate GBM progression under hypoxic conditions. Methods: Transcriptome sequencing, single-cell RNA sequencing, and spatial transcriptomic analyses were performed to explore the correlation between hypoxia and GAMs. Clinical samples were used to validate the findings. The underlying molecular mechanisms were examined via chromatin immunoprecipitation, quantitative real-time polymerase chain reaction, Western blotting analysis, and immunofluorescence assays. The therapeutic effectiveness was assessed via the use of in vivo models. Results: A subset of GAMs with elevated osteopontin (OPN) expression accumulates in response to hypoxic stimulation. Hypoxia induces OPN expression in macrophages via the histone 3 lysine 4 trimethylation-WD40 repeat-containing protein 5 (H3K4me3-WDR5) epigenetic axis. These OPN-positive GAMs (OPN⁺ GAMs) enhance the mesenchymal transition in GBMs by secreting OPN into the TME. Mechanistically, OPN activates nuclear factor κB (NF-κB) signaling through cluster of differentiation 44 (CD44), subsequently leading to increased programmed cell death ligand 1 (PD-L1) expression. The inhibition of OPN increased GBM sensitivity to temozolomide (TMZ) in orthotopic models. Conclusions: This study revealed the potential mechanism by which hypoxia-induced OPN⁺ GAMs promote the mesenchymal transition in GBM cells and demonstrated the therapeutic potential of targeting OPN to enhance TMZ treatment effectiveness.

Tumor-associated stromal cells (TASCs) are key architects of the tumor microenvironment (TME), playing a vital role in tumor development, metastasis, and therapeutic response. Their spatiotemporal heterogeneity, characterized by dynamic phenotypic plasticity, diverse cellular subtypes, and distinct spatial distributions, offers profound insights into tumor behavior and paves the way for innovative therapy development. In particular, stromal-immune interactions reveal the powerful capacity of TASCs to shape the immune landscape, highlighting their potential as targets in immunotherapy. Despite growing evidence in functional diversity, precise mechanisms underlying the temporal evolution and spatial organization of TASCs remain elusive, impeding clinical translation. This review delved into the molecular signatures and functional states of TASCs, emphasizing their roles in tumor dynamics and therapeutic resistance. We also discussed innovative strategies targeting the plasticity of TASCs to reverse immune evasion and potentiate immune-mediated tumor eradication. Future studies should prioritize identifying spatially resolved and mechanically defined biomarkers with multi-omics and machine learning approaches, enabling a comprehensive understanding of TASCs to bridge the gap from bench to bedside.

The cover image is based on the article RNA m¹A methyltransferase TRMT61A promotes colorectal tumorigenesis by enhancing ONECUT2 mRNA stability and is a potential therapeutic target by Huarong Chen et al., https://doi.org/10.1002/cac2.70070.