Precise mechanisms underlying breast cancer (BrCa) metastasis are undefined, which becomes a challenge for effective treatments. Chemokine signaling instigates the trafficking of cancer cells in addition to leukocytes. This study aimed to ascertain the clinical and biological significance of the CXCR6/CXCL16 signaling axis in the pathobiology of BrCa. Our data show a higher expression of CXCR6 in BrCa cell lines and tissues. Stage-III BrCa tissues express significantly higher CXCR6 compared to stage-II tissues. The ligand, CXCL16, could remain tethered to the cell surface, and, after proteolytic shedding of the ectodomain, the N-terminal fragment is released, converting it to its oncogenic, soluble form. Like CXCR6, N-terminal CXCL16 and ADAM-10 were significantly higher in stage-III than stage-II, but no significant difference was observed in the C-terminal fragment of CXCL16. Further, stimulation of the CXCR6/CXCL16 axis activated Src, FAK, ERK1/2, and PI3K signaling pathways, as per antibody microarray analysis, which also underlie CXCL16-induced F-actin polymerization. The CXCR6/CXCL16 axis induces cytoskeleton rearrangement facilitating migration and invasion and supports BrCa cell survival by activating the PI3K/Akt pathway. This study highlights the significance of the CXCR6/CXCL16 axis and ADAM10 as potential therapeutic targets for advanced-stage BrCa.

Assembled virus-like particles (VLPs) without genetic material, with structure similar to infectious virions, have been successfully used as vaccines. We earlier described in vitro assembly, characterisation and tissue specific receptor dependent Clathrin mediated entry of empty HEV VLPs, produced from Escherichia coli expressed HEV capsid protein (pORF2). Similar VLP’s have been described as a potential candidate vaccine (Hecolin) against HEV. We have attempted to use such recombinant assembled Hepatitis E virus (HEV) VLPs as a carrier for heterologous RNA with protein coding sequence fused in-frame with HEV 5′ region (containing cap and encapsidation signal) and investigated, if the relevant protein could be expressed and elicit an immune response in vivo. In vitro transcribed red fluorescent protein (RFP)/Hepatitis B virus surface antigen (HBsAg) RNA, fused to 5′-HEV sequence with cap and encapsidation signal (1–249 nt), was packaged into the recombinant HEV-VLPs and incubated with five different cell lines (Huh7, A549, Vero, HeLa and SiHa). The pORF2-VLPs could specifically transfer exogenous coding RNA into Huh7 and A549 cells. In vivo, Balb/c mice were immunized (intramuscular injections) with 100 µg pORF2-VLP encapsidated with 5′-methyl-G-HEV (1–249 nt)-HBsAg RNA, blood samples were collected and screened by ELISA for anti-pORF2 and anti-HBsAg antibodies. Humoral immune response could be elicited in Balb/c mice against both HEV capsid protein and cargo RNA encoded HBsAg protein. These findings suggest that other than being a possible vaccine, HEV pORF2-VLPs can be used as a promising non-replicative tissue specific gene delivery system.

This Research Topic integrates evidence from four original research investigations and four cutting edge review manuscripts that collectively highlight the emerging convergence between therapeutic strategies, tumor biology and the gut microbiome in colorectal (CRC). Together, these contributions integrate real-world clinical evidence with conceptual advances that advance the framework for personalized and precision management of CRC.Zhang et al. presented a three-arm retrospective study comparing conventional chemoradiotherapy, total neoadjuvant therapy (TNT), and PD-1-based immunotherapy in locally advanced rectal cancer (LARC). Their findings indicate that incorporating TNT or immunotherapy into the neoadjuvant regimen enhances pathological response and tumor downstaging, bolstering evidence for a paradigm shift toward intensified multimodal therapy. Yet, the study also exposes key diagnostic limitations, including inconsistent MRI restaging accuracy and restricted microbiome sampling, which hinder robust biomarker validation. The authors emphasize the need for multicenter, prospective investigations combining radiomics and microbiome profiling to advance precision in treatment response prediction.Extending this biological continuum, Wang et al. delineated profound gut microbial dysbiosis in CRC, marked by enrichment of pro-tumorigenic taxa Fusobacterium and Peptostreptococcus. The study's integrative analysis connects these microbial profiles with oncogenic gene expression signatures (TIMP1, BCAT1, TRPM4, MYBL2), suggesting the role of a coordinated microbiota-gene network shaping CRC progression. Although limited by sample size and cross-sectional design, these results strengthen the growing recognition of the gut microbiome as a biomarker reservoir and a modifiable therapeutic target in colorectal carcinogenesis.However, the absence of functional and metabolomic validation constrains mechanistic insight, underscoring the need for larger longitudinal multi-omics studies to establish causality and therapeutic relevance. Similarly, Kushwaha et al. performed a culture-based study in Indian CRC patients wherein potentially pro-tumorigenic genera were enriched including Enterococcus, Escherichia, Klebsiella, and Veillonella compared with adjacent normal mucosa. Isolation of 75 viable strains from paired sites underscores the value of cultivable bacteria as experimentally tractable candidates to interrogate inflammation, carcinogenesis and develop a specific microbial profile. Findings here reinforce the utility of gut microbiome as a reservoir of putative diagnostic markers and targets for microbiotamodulating interventions. However, the small cohort size, single-center setting, and exclusive reliance on culture constrain generalizability and likely underestimate microbial diversity. Larger, longitudinal studies integrating culture with sequencing-based profiling are needed to distinguish microbial drivers from passengers in colorectal cancer.Complementing these findings from the upper GI tract, Qian et al. applied a multi-omics approach to Gastric Cancer (GC), revealing that microbiome-associated epigenetic dysregulation may underlie gastric tumorigenesis. Six key hub genes (CDK1, CDK2, NOXO1, CUL1, MAPK1, CCNB1) emerged as consistently altered across transcriptomic and methylation datasets, with functional validation in GC cell lines. This work broadens the molecular framework linking microbial influence on gene regulation in GC and highlights novel candidates for biomarker and drug development. However, as with related studies, the lack of direct patient microbiome data and mechanistic exploration underscores the current gap between computational inference and biological validation.Taken together, these investigations illuminate the dynamic interplay between external microbial ecosystems and internal tumor epigenetics, with therapeutic implications spanning the GI axis. As immunotherapy continues to be incorporated into earlier disease settings and microbiome research matures into interventional science, an integrated systems approach will be essential. Future research must bridge clinical oncology with microbiome and epigenetic biology through harmonized, longitudinal, multi-omics trials. The convergence of these domains heralds a new era of precision GI oncology, one that not only targets the tumor but also the microbial and molecular landscapes that shape its evolution.The accompanying review articles converge on a unifying message. The gut microbiome is a central, actionable driver of colorectal cancer biology, simultaneously shaping tumor initiation, progression and therapeutic response through tightly interwoven immune, metabolic and barrier mechanisms. Dysbiosis, marked by loss of butyrate-producing commensals and overgrowth of pathobionts such as Fusobacterium nucleatum, enterotoxigenic Bacteroides fragilis and toxigenic E. coli, emerge as both initiator and amplifier of malignant evolution thereby linking diet, sex hormones and host genetics to DNA damage, epigenetic rewiring, chronic inflammation and an immunosuppressive niche. In parallel, commensal-derived short-chain fatty acids and selected probiotics exert opposing, tumor-constraining effects, while the same microbial circuits that govern carcinogenesis also gatekeep efficacy and toxicity of chemotherapy, radiotherapy and immune checkpoint blockade. This aids in the positioning of microbiome-informed biomarkers and microbiota-targeted interventions (including probiotics and fecal microbiota transplantation) as integral components of future precision prevention and therapy in CRC.Viewed as a whole, clinical response in CRC is jointly determined by therapeutic regimen, intrinsic tumor features, host immunity and the gut microbiota. Current response assessment tools remain poorly calibrated to this complexity. The integration of outcome-oriented clinical studies with mechanistic reviews heightens translational...

Pulmonary fibrosis (PF) is a progressive lung condition characterized by irreversible scarring and high mortality, with limited effective treatments. Mitochondrial dysfunction has emerged as a critical factor in fibroblast activation in PF, although approaches to restore mitochondrial function remain underexplored. The present study investigated whether mitochondrial transfer from alveolar type II epithelial cells (A549) to patient-derived fibroblasts could restore mitochondrial function and bioenergetics. Histological analysis of fibrotic lungs reveals increased collagen deposition and elevated profibrotic markers, accompanied by reduced expression of mitochondrial biogenesis and respiratory proteins compared to non-fibrotic controls, indicating mitochondrial impairment. Freshly isolated donor mitochondria were functionally validated before mitoception using Seahorse analysis and patient-derived fibroblasts were confirmed by qRT-PCR using fibroblast-specific markers. In vitro transfer of mitochondria to diseased patient-derived fibroblasts exhibited a modest, dose and time-dependent increase in mitochondrial membrane potential compared to normal fibroblasts. Gene expression analysis revealed decreased fibrosis-associated markers and increased expression of mitochondrial and antioxidant genes following mitoception. Seahorse analysis after mitoception revealed enhanced ATP-linked respiration and improved selected mitochondrial bioenergetic parameters, whereas maximal respiration and spare respiratory capacity demonstrated variable responses. In contrast, normal fibroblasts displayed minimal changes. Collectively, these findings indicate that mitochondrial transfer modulates fibroblast bioenergetics and profibrotic signaling, supporting its potential as a therapeutic strategy for pulmonary fibrosis.