Background Platinum resistance remains the principal obstacle to improving survival in ovarian cancer. Microvascular invasion (MVI) is associated with chemoresistance and immune remodeling, but the molecular regulators connecting vascular invasion, innate immune-driven inflammatory amplification, and treatment failure remain poorly defined. Methods Three public datasets and 118 literature-curated MVI genes were integrated. Differential expression analysis followed by three-way intersection identified PAQR5 as the core candidate. Its clinical, immune-inflammatory, and pharmacological relevance was mapped using CIBERSORT, ESTIMATE, pRRophetic, and nomogram modeling, and validated by qPCR/Western blot, MTT/CCK-8, colony/wound-healing assays, flow cytometry, gamma-H2AX foci, EdU incorporation, and subcutaneous xenografts (n = 5–6 mice/group). Results PAQR5 was the only gene shared among cisplatin-resistance signatures in vitro (303 DEGs), patient tissue resistance signatures (2507 DEGs), and the MVI gene set. TCGA tumors overexpressed PAQR5 2.8-fold compared with GTEx normal tissue (P < 0.001). High PAQR5 independently predicted shortened overall survival (HR = 1.18; 95% CI 1.02–1.44; P = 0.005) and 5-year progression-free survival (HR = 1.33; 95% CI 1.09–1.63; P = 0.04). In silico, PAQR5-high tumors showed an innate immune-skewed suppressive profile, with increased M2 macrophages (+28%) and Tregs (+17%) but reduced CD8+ T cells (-31%) and NK cells (-21%; all P < 0.01). They also displayed elevated cisplatin, docetaxel, and paclitaxel IC50 values (each P < 0.0001), whereas AKT-inhibitor VIII IC50 fell 1.7-fold. Functionally, PAQR5 overexpression increased proliferation, colony formation, migration, DNA damage tolerance, and xenograft growth, whereas silencing produced mirror-image suppression and restored cisplatin-induced apoptosis. Conclusion PAQR5 appears to couple MVI with platinum resistance by coordinating an immunosuppressive inflammatory tumor microenvironment, enhanced DNA damage repair, and reduced apoptosis. These findings nominate PAQR5 as a mechanism-linked biomarker and a therapeutic entry point for targeting inflammation-associated chemoresistance in ovarian cancer.
Biglycan (BGN) is an important component of the extracellular matrix (ECM). Using an integrated analysis of TCGA bulk RNA-sequencing, single-cell RNA-sequencing, and spatial transcriptomic datasets, we systematically characterized the expression patterns, prognostic significance, and biological roles of BGN in head and neck squamous cell carcinoma (HNSCC). Western blotting, immunohistochemistry, and survival analyses in independent clinical cohorts further validated the expression pattern, abundance, and prognostic significance of BGN. The biological role of BGN was further investigated using in vitro tumor cell–cancer-associated fibroblasts (CAFs) co-culture systems, BGN knockdown, and subsequent phenotypic assays. Here, BGN was significantly upregulated in HNSCC tissues, and elevated BGN expression was associated with poorer patient prognosis. Higher BGN expression was also associated with increased mesenchymal scores, enrichment of pathways related to CAF activation, ECM remodeling, and epithelial–mesenchymal transition (EMT), as well as potentially reduced sensitivity to commonly used chemotherapeutic agents. Single-cell transcriptomic analysis revealed that BGN was predominantly expressed by CAFs, with BGN-positive (BGN+) CAFs exhibiting markedly enhanced ECM remodeling activity and greater potential for intercellular communication. Spatial transcriptomic analysis further demonstrated that BGN-high spots were preferentially localized within the stromal matrix and distant from the tumor core. Functionally, tumor cells co-cultured with BGN-knockdown CAFs exhibited reduced proliferation, colony-forming capacity, invasion, and migration, accompanied by suppression of the EMT phenotype. Collectively, these findings suggest that BGN may serve as a biomarker of an ECM/stromal remodeling–dominant CAF state in HNSCC and represent a potential therapeutic target for HNSCC.
Background Chemotherapy combined with programmed cell death protein-1 (PD-1) antibody immunotherapy has become the standard first-line treatment for most patients with malignant solid tumors. However, data from multiple phase III trials indicate that even with first-line induction followed by immunotherapy maintenance, median progression-free survival (PFS) remains less than one year. Methods In this phase I dose-escalation trial (3 + 3 design), 12 patients who completed six cycles of first-line chemoimmunotherapy received oral fecal microbiota transplantation (FMT) capsules plus anti-PD-1 maintenance immunotherapy at escalating dose levels (i to i + 3). The primary endpoint was safety; secondary endpoints included the recommended phase II dose (RP2D), PFS, and disease control rate (DCR). Fecal and blood samples were collected for exploratory microbiome and metabolomic analyses. Results No grade ≥3 FMT-related toxicities occurred. With a median follow-up of 36.9 months, median PFS was 19.8 months (95% CI 11.2–28.4); maintenance-phase PFS was 11.7 months (95% CI 4.1–19.3). 4 patients remained progression-free on continued immunotherapy. Four patients (33.3%) experienced grade 1–2 gastrointestinal events. Microbiomic analyses showed post-FMT expansion of Blautia and Faecalibacterium, with dose level i + 1 demonstrating the greatest α-diversity shift and engraftment rate. Metabolomic analysis showed that serum arachidonic acid levels increased after FMT. Conclusion Oral FMT combined with immunotherapy as first-line maintenance therapy for solid tumors was safe and well tolerated, showed promising preliminary efficacy, and induced favorable compositional changes in the gut microbiota. This study was registered with the Chinese Clinical Trial Registry (Registration No.: ChiCTR2100054928).
Although immune checkpoint inhibitors have revolutionized cancer treatment, therapeutic resistance and heterogeneous patient responses remain major clinical challenges. Current paradigms predominantly focus on amplifying effector T cells (Teffs); however, this approach frequently encounters structural bottlenecks imposed by a tumor-locked, suppressive immune homeostasis. Central to this aberrant equilibrium are regulatory T cells (Tregs), which persistently elevate immune activation thresholds and restrict durable antitumor responses. In this review, we propose a paradigm shift toward reshaping baseline T cell homeostasis, highlighting exercise as a potent, systemic physiological intervention. Regular exercise systematically counteracts tumor-induced homeostatic locking by reprogramming immune metabolism, attenuating chronic inflammation, and improving tissue perfusion. Rather than indiscriminately depleting Tregs, exercise dynamically recalibrates the Teff/Treg balance, lowering activation thresholds while preserving systemic immune tolerance. Furthermore, we propose that structured physical activity may support a form of “homeostatic memory,” with potential implications for the durability of immunotherapy responses. Integrating exercise into oncological care offers a translational, host-centered strategy to optimize the immune background, thereby unlocking the full clinical potential of cancer immunotherapy.
Clear cell renal cell carcinoma (ccRCC) is characterized by high aggressiveness and limited therapeutic options. However, the molecular determinants driving ccRCC progression and therapeutic vulnerability remain incompletely defined. Through integrated bulk and single-cell transcriptomic analyses, we identified HAUS5 as a tumor-enriched factor that was highly expressed in ccRCC tissues and tumor-derived epithelial cells. Elevated HAUS5 expression was associated with adverse clinicopathological features and poor overall survival. Functional assays showed that HAUS5 depletion suppressed ccRCC cell proliferation, migration, invasion, and xenograft tumor growth. Mechanistically, HAUS5 was associated with MAPK/ERK signaling activation and epithelial–mesenchymal transition, whereas EGF partially rescued the inhibitory effects induced by HAUS5 knockdown. In addition, drug sensitivity analysis identified Belinostat as a candidate compound associated with HAUS5 expression, and functional experiments showed that Belinostat attenuated HAUS5-associated malignant phenotypes. Collectively, these findings suggest that HAUS5 contributes to ccRCC progression through a MAPK/ERK-associated EMT program and may be linked to differential sensitivity to Belinostat.
