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The DNA sensing signaling pathway mediated by cGAS-STING has achieved significant progress in cancer therapy. However, the role of the RNA sensing signaling pathway mediated by RLRs-MAVS in cancer has been relatively underexplored. In this review, we first elaborate on the structural basis, activation, and regulatory mechanisms of MAVS, and examine its functional interplay with other innate immune pathways. We then comprehensively review its functions in cancer. Finally, we summarize its potential clinical applications, existing challenges, and proposed solutions. Moreover, we compare MAVS with STING across these three dimensions and find that they exhibit similarities in signaling pathways, perform analogous functions in cancer, and share comparable potential for clinical applications. Therefore, we propose that MAVS could emerge as the next STING in cancer therapy.
It is estimated that ∼170,000 women in the US live with metastatic breast cancer in 2025. While multiple treatment options exist for metastatic breast tumor, none of them are curative. Here, we investigate the mechanism through which S100A4 promotes breast cancer metastases and report that S100A4 is a critical regulator of neutrophil infiltration into the lung to establish a premetastatic niche (PMN). We show that a novel S100A4 blocking antibody (S100A4-11) suppresses neutrophil infiltration and relieves TIGIT-mediated NK cell inhibition in the lung, leading to significantly reduced lung metastases in two different mouse models. When the treatment is initiated after the PMN formation, simulating most clinical situations, S100A4-11 treatment as a monotherapy is not sufficient to block lung metastases. However, a novel combination of anti-S100A4 and anti-TIGIT treatment significantly suppresses late-stage lung metastases by increasing CD8+ T and NK cell infiltration and activation in the lung. In summary, this study provides compelling evidence that S100A4 functions systemically and locally to promote breast cancer metastases and supports developing S100A4-11 as a novel immunotherapy to suppress breast cancer metastases.
In 2021, the Commission on Cancer implemented Standard 5.8 requiring lymph node sampling from ≥3 mediastinal and ≥1 hilar stations (3N2+1N1) during curative-intent lung cancer resections. Before Standard 5.8, sampling ≥10 lymph nodes was recommended. To date, the optimal nodal sampling strategy is still unknown, particularly for sublobar resections. We assessed 3N2+1N1 sampling patterns and potential associations with recurrence and mortality by resection type. In this multicenter retrospective study, we evaluated early-stage non-small cell lung cancer (NSCLC) patients who underwent lobectomy or sublobar resection (2009-2019). We calculated the proportion with 3N2+1N1 sampled. Using multivariable Cox regression, we assessed associations of 3N2+1N1 sampling with 1-year recurrence and 5-year overall mortality, stratified by lobectomy vs sublobar resection. Among 2096 lobectomy patients, 43% had 3N2+1N1 sampling. In contrast, among 386 sublobar resection patients, 23% had 3N2+1N1. We found 3N2+1N1 sampling was not significantly associated with 1-year recurrence or 5-year mortality after lobectomy, but was associated with reduced 1-year recurrence (adjusted hazard ratio, 0.62; 95% CI, 0.39-0.98) after sublobar resection. A minority of lobectomy and sublobar resection patients had 3N2+1N1 sampling. Although 3N2+1N1 sampling was not associated with improvements across all outcomes, our findings suggest that Standard 5.8 may be a meaningful step toward improved quality of lymph node evaluations in some patients.
Lung cancer is strongly associated with increased extracellular matrix (ECM) stiffness, which correlates with poor patient prognosis. Our study reveals that high-stiffness tumor niches exhibit significant upregulation of neutrophil extracellular traps (NETs), which enhance the Warburg effect and promote tumor cell proliferation. Using atomic force microscopy (AFM) and multi-immunofluorescence staining (mIF), we demonstrated a spatial correlation between NETs formation and localized ECM stiffness in lung cancer tissues. In KrasLSL-G12D/+/Trp53 fl/fl transgenic mouse model, bleomycin-induced lung stiffening further increased NETs generation, while genetic ablation of Pad4 (Pad4-/- mouse model) or pharmacological inhibition of NETs (via LOX mAb, BAPN, or DNase I) reduced tumor burden. Mechanistically, stiffness-driven NETs upregulated glycolytic enzymes and extracellular acidification rate (ECAR) through aberrant mTOR pathway activation. Ex vivo and patient-derived xenograft (PDX) models validated the therapeutic potential of targeting LOX could extracellularly attenuate stiffness of ECM and intracellularly inhibit mTOR pathway. Our findings propose a novel strategy to improve lung cancer outcomes by disrupting the stiffness-NETs-mTOR axis, offering a one target-dual function approach for tumors with stiffening ECM.
Neoadjuvant therapy (NAT) has emerged as a standard treatment strategy for locally advanced breast cancer (BC), yet robust biomarkers for response prediction remain elusive. Here, we established a real-world NAT cohort of 1161 Chinese BC patients, including 1145 cases with matched clinicopathological data and targeted sequencing, to systematically evaluate genomic features associated with NAT outcomes. We identified both cross-subtype and subtype-specific genomic associations with treatment response. PI3K-pathway alterations emerged as a consistent feature of resistance across subtypes, whereas mutations such as ERBB2 in HER2+ disease and MAP3K1 in triple-negative breast cancer were associated with subtype-specific response patterns. Regimen-level analyses further showed that some genomic associations were treatment-context dependent across chemotherapy-, endocrine-, anti-HER2-, and immunotherapy-containing regimens. Among patients with non-pathological complete response (non-pCR), genomic profiling further refined risk stratification for distant recurrence by revealing subtype-specific prognostic alterations, including TOP3B and SETD2. Furthermore, a machine-learning model integrating genomic and clinicopathological features showed favorable performance for NAT response prediction. Overall, our study provides a comprehensive genomic framework for response prediction and recurrence risk assessment, supporting more precise stratification and biomarker-guided treatment optimization in Asian breast cancer patients.
Lack of DNA double-strand break repair efficiency exquisitely sensitizes cancers to poly-ADP ribose polymerase inhibitors (PARPi). Unfortunately, resistance to PARPi poses an insurmountable challenge for patients. Mechanisms that confer insensitivity to PARPi therapy include enhanced DNA damage repair and autophagy. Natural and non-natural unsaturated fatty acid nitroalkene derivatives (NFA) show anticancer actions that sensitize TNBC cells to PARPi and other DNA-damaging treatments. We reveal that nitro-oleic acid (OA-NO2) re-sensitizes PARPi-resistant TNBC cells to PARPi. RNA-seq analysis of clinically relevant mutBRCA1 PARPi-resistant TNBC cell lines exhibited upregulation in autophagy and lysosomal pathways. Bio-orthogonal analysis identified the autophagy regulator SQSTM1/p62 as a novel OA-NO2 target, alkylating two redox-sensitive Cys residues of p62 (Cys105 and Cys113). These Cys are essential for p62 regulation of autophagy and mimicked the effects of p62 Cys105 and Cys113Ala mutants and when alkylated by OA-NO2 showed impaired p62 oligomerization, degradation, and inhibition of autophagy. Combination treatment of PARPi-resistant TNBC with a PARPi and OA-NO2 identified the most synergistic HSA scores and inhibited p62-associated autophagy and lysosome function. These data underscore the clinical potential of OA-NO2 for treating PARPi-resistant TNBC patients.
Early prediction of treatment response during neoadjuvant therapy (NAT) is crucial for timely therapeutic adjustments in breast cancer. Jointly capturing dynamic tumor evolution from longitudinal imaging and tumor microenvironmental cues from biopsy enables improved predictive performance and fosters the development of a personalized tool to assist clinicians in managing NAT. We proposed a multimodal framework, RePALM, which integrated clinical information, pre-NAT MRI, biopsy pathology, and post-2cycle MRI. It was developed and validated on 2604 patients from four retrospective cohorts and further evaluated in a prospective cohort of 72 patients (ChiCTR.org.cn, ChiCTR2400079698). The stepwise integration strategy enabled assessment of the incremental value of each modality. Model performance was benchmarked against radiologists in a reader study, and its predictions were further integrated with RECIST 1.1 for exploratory response stratification. Transcriptomic analysis was conducted to provide biological interpretability. RePALM demonstrated consistent performance across retrospective and prospective validation cohorts, with AUROC of 0.8730-0.8970 and AUPRC of 0.7450-0.8140. After two NAT cycles, RePALM identified ∼90% of non-pCR patients, enabling early consideration of surgical intervention or trial enrollment. We further demonstrated that stepwise incorporation of multimodal information markedly enhances predictive accuracy. The model also improved assessment performance for junior radiologists. RePALM-derived scores were independently prognostic for event-free survival, while transcriptomic analysis revealed enrichment of treatment-sensitivity pathways, underscoring biological plausibility. RePALM integrates longitudinal imaging and biopsy pathology to predict early NAT response, with demonstrated associations with survival and underlying biological processes, supporting its potential utility in individualized management of breast cancer.
The therapeutic efficacy of systemic treatments in cancer therapy is invariably limited by the biophysical barriers, including vascular endothelial barrier, extracellular matrix, and elevated interstitial fluid pressure. Ultrasonic cavitation, as a non-invasive modality, can induce a series of biological effects that leverage mechanical forces to breach these biophysical barriers and remodel the tumor microenvironment. This review traces the paradigm shift from thermal coagulation to mechanochemical modulation, where acoustic forces are transduced into profound biological responses via mechanosensitive ion channels and immunogenic signaling pathways. We summarize recent advances in the intelligent engineering of ultrasound-active materials, from vascular-targeted microbubbles and phase-change nanodroplets to oxygen-independent piezocatalysts. Meanwhile, we clinically evaluate the utility of cavitation in enhancing drug delivery and remodeling immune environment, and highlight the milestone approval of histotripsy for non-thermal ablation. Finally, we discuss critical challenges regarding stochasticity and biosafety, proposing a roadmap toward artificial intelligence-guided, closed-loop dosimetry. We predict that by integrating physical mechanics with biological engineering, ultrasonic cavitation may alleviate multidrug resistance and immunosuppression in cancer therapy.
Following the publication of the above paper, it was drawn to the Editor's attention by a concerned reader that Fig. 6A on p. 320, showing the tumor volumes from the in vivo experiments, was lacking the units in the y‑axis, hence undermining the ability to usefully interpret the data in this figure part. In addition, after having performed an independent assessment of the data in this paper in the Editorial Office, it came to light that western blot data in Fig. 2D and flow cytometric plots in Fig. 3A appeared subsequently in different papers in different experimental contexts, one written by different authors in 2018 in the journal Journal of Experimental and Clinical Cancer Research, and the other featuring an author named Cong Long in the journal Oncology Letters. The authors have been contacted by the Editorial Office to offer an explanation for the concerns that have been identified in their paper, and we are awaiting their response. Owing to the fact that the Editorial Office has been made aware of potential issues surrounding the scientific integrity of this paper, we are issuing an Expression of Concern to notify readers of these potential problems while the Editorial Office continues to investigate this matter further. [Oncology Reports 37: 313‑322, 2017; DOI: 10.3892/or.2016.5286].
Bone metastatic pain in lung cancer remains difficult to control and its molecular drivers are incompletely defined. Here, integrating a clinical cohort with mechanistic models, we delineate a tumor metabolism-neural epigenetic-ion-channel axis. In patients with lung cancer bone metastases, 63% reported moderate-severe pain, and higher preoperative VAS scores associated with shorter overall survival. Single-cell RNA-sequencing of metastatic lesions demonstrated glycolysis enrichment in tumor cells from patients with higher pain, and dorsal root ganglia (DRG) from these patients exhibited stronger pan-lysine lactylation, which positively correlated with VAS. In mice, a femoral Lewis lung carcinoma model recapitulated progressive mechanical allodynia, thermal hyperalgesia, locomotor impairment, systemic hyperlactatemia, and increased DRG lactylation. Intrathecal lactate in naïve mice induced DRG lactylation and hypersensitivity, whereas intrathecal oxamate in tumor-bearing mice attenuated both, establishing a causal role for lactate signaling. CUT&Tag profiling revealed a marked gain of H3K18 lactylation at the Trpm3 promoter in tumor DRG, with concordant upregulation of Trpm3 mRNA and TRPM3 protein; Trpm3-/- mice displayed blunted thermal and mechanical pain behaviors. Therapeutically, CT-guided microwave ablation (MWA) of femoral tumors produced significant analgesia and functional improvement, reduced DRG H3K18 lactylation and TRPM3, and, in vitro, suppressed tumor glycolytic proteins (HK2, MCT1, GLUT1). These findings identify a targetable lactate-H3K18 lactylation-TRPM3 pathway in bone metastatic pain and support MWA as a mechanism-based palliative strategy that modulates the metabolic-epigenetic drivers of nociceptor sensitization.
Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, yet their clinical application is constrained by a critical trade-off between potent antitumor efficacy and off-target cardiovascular toxicity. This adverse effect underscores a fundamental biological dilemma: how tumor immunotherapy disrupts cardiovascular homeostasis. Immune cells within the cardiovascular system undergo metabolic adaptations after immune therapy. This intricate crosstalk has brought metabolic checkpoints to the forefront of research. In this review, we systematically outline the features of tumor-associated metabolic remodeling and shared roles in cardiac metabolism and immunometabolism. We elucidate ICIs initiate a cascade of events leading to cardic dysfunction through metabolic signal pathways. Furthermore, we propose that the strategic integration of cutting-edge technologies including spatial metabolomics to enable precise reprogramming of metabolic networks will ultimately decouple the efficacy of cancer immunotherapy from its associated toxicities.
Androgen receptor (AR) pathway inhibitors (ARPIs) improve outcomes in advanced prostate cancer (PC) in combination with androgen deprivation therapy (ADT). However, PC rapidly develops ARPI resistance, frequently through expression of truncated AR variants (AR-Vs), like AR-V7, highlighting a need for more effective therapies. The sodium-glucose co-transporter 2 inhibitor (SGLT2i) canagliflozin, an approved diabetes drug, also suppresses PC growth and inhibits AR-related gene expression. Therefore, we hypothesized that canagliflozin may directly inhibit AR. Cellular and tumor models of PC were subjected to proliferation, clonogenic, and xenograft studies. RNA-seq and siRNA knockdown approaches defined molecular mechanisms. Molecular docking, thermal shift, and surface plasmon resonance assays assessed drug-target interactions. Stable sh-AR full-length (sh-AR-FL) and sh-AR-V7 cell lines were generated to interrogate the transcriptomic impact of AR and prognostic analysis was performed using clinical datasets. We found that canagliflozin suppresses PC growth through AR. It interacts with the AR ligand binding domain (LBD) with estimated affinity comparable to ARPIs and blocks AR signaling. Canagliflozin reduces the transcript and protein levels of the HSP70 chaperone and suppresses the cytoplasmic and nuclear levels of AR-FL and AR-Vs through proteasomal degradation. It mediates substantial reprogramming of PC transcriptional activity, including inhibition of AR pathway, cell-cycle, E2F and Myc hallmark targets. Its gene expression profile overlaps with silencing AR-FL or AR-V7 is associated with improved prognosis in clinical datasets. The results of this study demonstrate the potential for canagliflozin to function as a clinically useful ARPI and support prospective clinical investigation of this drug in PC.
Pancreatic adenocarcinoma (PAAD) is a highly lethal malignancy with limited prognostic biomarkers and therapeutic targets. Lactate-driven lactylation has recently emerged as an important regulator of cancer progression, but its role in PAAD remains unclear. In this study, integrative analysis of TCGA and GEO datasets, combined with experimental validation, identified a five-gene lactylation-associated signature (LRP3, TTLL6, TSGA13, PRKCG, and SDK2) that effectively stratified PAAD patients by survival risk. High-risk tumors displayed an immunosuppressive phenotype with reduced immune infiltration, Th2-skewed remodeling, checkpoint activation, and distinct mutational and drug-sensitivity features. Among the signature genes, PRKCG was significantly downregulated in PAAD and associated with advanced disease and worse prognosis. PRKCG overexpression inhibited tumor cell proliferation, migration, invasion, and xenograft growth, while enhancing apoptosis. Mechanistically, lactate-induced lactylation impaired PRKCG-dependent activation of the p53 pathway without altering PRKCG expression, and mutation of predicted lactylation sites partially rescued this effect. These findings define a lactylation-associated prognostic model for PAAD and highlight the lactate-PRKCG-p53 axis as a potential therapeutic vulnerability.
Colorectal cancer (CRC) is a common malignancy and a leading cause of morbidity and mortality worldwide. Taurine, a sulfur-containing amino acid derivative, has gained attention for its potential regulatory role in CRC. In addition, active metabolites, such as hydrogen sulfide produced by the interaction between taurine and intestinal microbiota, may influence CRC progression. This review systematically examines the role of the "taurine-gut microbiota" axis in the pathogenesis and treatment of CRC. We summarize the mechanisms by which taurine inhibits tumor proliferation, induces apoptosis, and enhances chemosensitivity. We also highlight its role in modulating the tumor immune microenvironment, maintaining intestinal barrier function, and preserving microbial homeostasis through microbiota-mediated metabolic regulation. Finally, we discuss translational strategies, including dietary interventions and taurine-based combination therapies, providing a new perspective for integrating taurine into CRC management.
Colorectal cancer (CRC) typically follows the "normal-adenoma-carcinoma" (NAC) progression, with approximately 70-90% of cases driven by an adenomatous polyposis coli (APC) mutation-dependent pathway. The Apc-mutant (Min) mouse, valuable for dissecting gene function and mechanisms in CRC, provides an important basis for cross-species analyses with human data. Here, we performed a cross-species analysis of single-cell and spatial transcriptomic data across multiple stages of colorectal tissues in both humans and Min mice, constructing a spatiotemporal atlas. Our study identified key microenvironmental regulatory networks involved in CRC progression and highlighted the central role of epithelial-macrophage interactions within the tumor microenvironment. We further validated the suitability of the Min mouse as a model for the intrinsic Consensus Molecular Subtypes 2(iCMS2) microsatellite-stable (MSS) subtype of CRC. Focusing on the crosstalk between tumor-associated macrophages (TAMs) and epithelial cells, we identified the EFNA1-EPHA4 axis as a critical regulator promoting the immunosuppressive polarization of TAMs and enhancing tumor cell stemness. In addition, inhibition of EFNA1 was found to slow tumor growth. This study not only provides a systematic framework for mapping CRC correspondence between humans and mice, but also uncovers key molecular mechanisms underlying CRC progression and proposes promising therapeutic targets.
KRAS-mutant colorectal cancer (CRC) exhibits an aggressive metastatic phenotype, largely driven by TGFβ-induced epithelial-mesenchymal transition (EMT). However, the downstream effectors mediating TGFβ-driven metastasis in this context remain incompletely defined. This study identifies interferon regulatory factor 2 (IRF2) as a key metastasis suppressor and direct transcriptional repression target of TGFβ-SMAD2/3 signaling. IRF2 expression is markedly downregulated at invasive tumor fronts, showing a significant inverse correlation with p-SMAD2 levels and advanced metastatic stage. Single-cell trajectory analysis reveals temporal IRF2 suppression precisely coinciding with TGFβ/EMT program activation during metastatic progression. Mechanistically, SMAD2/3 complexes directly bind the IRF2 promoter to mediate repression, and IRF2 overexpression effectively reverses TGFβ1-induced invasive phenotypes in vitro. Pharmacological TGFβR1 inhibition restores IRF2 expression, slowing tumor progression and extending survival in the KRAS-driven iKAP mouse model. Furthermore, IRF2 reconstitution potently inhibits CRC cell invasion and metastasis by transcriptionally repressing EMT-related genes and enhancing anti-tumor immunity, characterized by increased CD8+ T-cell infiltration and reduced regulatory T cells (Tregs). While active in various CRC contexts, the TGFβ-SMAD2/3-IRF2 axis is particularly critical in KRAS-mutant CRC, where IRF2 loss acts as a functional second hit to accelerate dissemination. These findings uncover a TGFβ-SMAD2/3-IRF2 axis governing EMT and metastatic dissemination, positioning IRF2 restoration as a promising therapeutic strategy for aggressive KRAS-mutant CRC.
Small cell lung cancer (SCLC) harbors pronounced intratumoral heterogeneity, yet epigenetic drivers of subtype plasticity remain poorly understood. Herein, we established paired neuroendocrine (NE)-high and NE-low SCLC organoids from pulmonary neuroendocrine cells (PNECs)-specific Trp53/Rb1/Pten-triple knockout mice. NE-high organoids developed prominent axon-like protrusions, while NE-low counterparts exhibited cystic structures. Both subtypes maintained primary tumor genetics and tumorigenicity. Transcriptomics revealed NE-high enrichment of neuronal programs versus innate immune pathway upregulation in NE-low organoids. Mechanistically, Polycomb repressive complex 2 (PRC2)-mediated H3K27me3 enrichment in NE-low organoids suppressed Dnmt3a, causing global DNA hypomethylation that reactivated endogenous retroviruses (ERVs), triggering cytosolic double-stranded RNA (dsRNA) accumulation and consequent antiviral interferon response. Notably, Carm1 stabilized Dnmt3a via transient methylation. Targeting Dnmt3a or Carm1 in NE-high organoids drove their transition to a NE-low state with ERV de-repression. Collectively, these findings establish a PRC2/CARM1/DNMT3A axis orchestrating SCLC plasticity, identifying DNA methyltransferase inhibition as a potential therapeutic strategy targeting SCLC heterogeneity and immunosuppression.
The efficacy of postsurgical immunotherapy for gastric cancer (GC) remains controversial, and the effect of the number of dissected lymph nodes (DLNs) on the efficacy of immunotherapy remains unknown. We retrospectively reviewed 451 patients who received adjuvant or palliative therapies (including immunotherapy and chemotherapy) for GC at nationwide centers between 2020 and 2025 to investigate the influence of DLNs on postsurgical immunotherapy. Prognoses were assessed based on DLNs. In the adjuvant immunotherapy cohort (n = 139), the disease-free survival (DFS) was significantly lower in patients with DLNs >36 compared with those with DLNs ≤36 [hazard ratio (HR), 2.62; 95% confidence interval (CI), 1.39-4.95, P = 0.003)]. Moreover, patients with DLNs≤36 who received combined immunotherapy had a better DFS than patients who received only adjuvant chemotherapy (HR, 0.37; 95% CI, 0.17-0.78, P = 0.006). In the palliative immunotherapy cohort (n = 47), patients with DLNs>36 had significantly lower progression-free survival (PFS) (HR, 3.57; 95% CI, 1.61-7.94, P = 0.001) and DCR (6.67% vs 65.6%, P < 0.001) than those with DLNs≤36. Additionally, when matching with patients who received palliative immunotherapy without previous gastrectomy (DLNs = 0), the PFS decreased progressively in patients with DLNs = 0, DLNs>0 to ≤36, and DLNs>36 (median PFS, 16 vs. 11 vs. 3 months, P = 0.002). In conclusion, excessive lymph node dissection (DLNs≥36) compromised the efficacy of postsurgical adjuvant or palliative immunotherapy for GC.
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