Melanoma remains a lethal malignancy with frequent resistance to immune checkpoint blockade therapy. Clinical evidence associates elevated PAK4 expression with poor response to anti-PD-1 treatment in melanoma patients. While tumor-derived exosomes are recognized as key immunosuppressive mediators, the role of PAK4 in regulating exosome secretion to induce immunosuppression remains incompletely understood. Here, we demonstrate that PAK4-mediated phosphorylation of Annexin-A2 (ANXA2) at Ser26 promotes its nuclear-to-cytoplasmic translocation, facilitating the formation of S100A10-ANXA2 heterotetramers that drive multivesicular body docking to the plasma membrane. Furthermore, PAK4 stabilizes synaptotagmin-1 by suppressing Trim21-mediated ubiquitin degradation, enabling SNARE complex assembly for membrane fusion. PAK4-driven exosomes exhibit potent immunosuppressive activity, substantially reducing CD8⁺ T cell numbers and impairing their function in mouse models. Notably, melanoma cells with high PAK4 expression secrete PD-L1-enriched exosomes that promote systemic immune evasion. In patient-derived xenograft models, pharmacological inhibition of PAK4 attenuates tumor progression and reduces circulating exosomal PD-L1 levels. Our study unveils a dual mechanism through which PAK4 drives exosome-dependent immunosuppression, providing a rationale for combining PAK4 pathway inhibitors with immune checkpoint blockade and offering translational strategies to overcome melanoma immunotherapy resistance.

Nanotechnology has transformed vaccine development by engineering nanovaccines that offer precise control over antigen performance, immune modulation and targeted delivery. These platforms influence physicochemical properties size, charge, and ligand expression to direct antigen trafficking, co-deliver adjuvants and antigen-presenting cells, stimulating potent and robust adaptive immune responses. This review discusses the development of nanovaccines for prophylactic vaccines which induce antibody and memory B-cell responses and therapeutic cancer vaccines, which overcome tolerance and immunosuppression to activate CD8⁺ T cells with particular emphasis on lipid nanoparticles (LNPs), polymeric NPs, inorganic-core NPs, virus-like particles (VLP) and mechanisms by which each platform exploits physicochemical properties to enhance the antigen encapsulation, adjuvant incorporation, lymphatic transferring, quality and quantity of adaptive immune responses. We reviewed the clinical and preclinical developments of these nanovaccine platforms in cancer and infectious disease immunotherapy, including major successes and new opportunities that will shape the future of vaccines for prevention and treatment.

To evaluate the diagnostic performance of spectral imaging for differentiating intrapancreatic accessory spleen (IPAS) from hypervascular pancreatic neoplasms using portal-venous phase (PVP) spectral CT.

This retrospective study included patients with hypervascular pancreatic lesions identified on PVP spectral CT. Lesion and splenic densities were measured on conventional images, virtual monochromatic images (VMI; 40-140 keV), virtual non-contrast (VNC) images, iodine maps, and effective atomic number (Z_eff) maps. Relative lesion-to-spleen ratios (RLSRs), with values closer to zero indicating greater similarity to the spleen, were compared between IPAS and neoplasms; diagnostic performance in the whole cohort and among patients with pancreatic tail lesions was assessed using the area under the receiver operating characteristic curve (AUC). For pancreatic tail lesions, three radiologists visually graded IPAS likelihood using conventional imaging alone and conventional imaging plus spectral imaging. Pooled sensitivity/specificity/accuracy and intraclass correlation coefficients (ICCs) were used to evaluate visual discriminative performance and inter-observer reproducibility, respectively.

Eighty-five patients (median age, 63.0 [IQR: 56.0-73.0] years; 45 men) with 34 IPAS and 51 neoplasms (34 IPAS and 22 neoplasms in the pancreatic tail) were included. RLSRs were lower in IPAS than in neoplasms across all image series (p < 0.001). In the whole-cohort/pancreatic-tail subgroup, AUCs of RLSR on conventional imaging, VNC, 40-keV VMI, iodine density, and Z_eff were 0.799/0.737, 0.835/0.899, 0.950/0.972, 0.960/0.980, and 0.969/0.992, respectively. In visual assessment, conventional plus spectral imaging improved pooled sensitivity/specificity/accuracy and ICC compared with conventional imaging alone (86.3%/90.9%/88.1% vs. 61.8%/59.1%/60.7%, 0.929 vs. 0.649, all p < 0.001).

Spectral imaging may facilitate differentiation of IPAS from hypervascular pancreatic neoplasms using only portal-venous-phase CT.

Question Can spectral imaging applied to hypervascular pancreatic lesions differentiate intrapancreatic accessory spleen (IPAS) from hypervascular neoplasms when only a single contrast-enhanced phase is available? Findings Use of spectral imaging yielded higher quantitative and qualitative performance for differentiating IPAS from neoplasms than conventional imaging, with better interobserver reproducibility in visual assessment. Clinical relevance Evaluating spectral properties may facilitate discrimination of IPAS from hypervascular pancreatic neoplasms identified on routine portal venous phase CT that would otherwise remain indeterminate on conventional CT and require additional diagnostic procedures.

Oral squamous cell carcinoma (OSCC), the most prevalent histological subtype of oral cancer, is characterized by an immunosuppressive tumor microenvironment (TME) predominantly modulated by tumor-associated macrophages (TAMs). The CXCL9/SPP1 ratio (CS ratio) has been validated as a more reliable prognostic biomarker than the conventional M1/M2 classification. Although methyltransferase-like 14 (METTL14) participates in TAM polarization, its specific role in regulating the CS balance in OSCC remains elusive. This investigation elucidates the mechanism by which METTL14 modulates TAM CS polarization and affects OSCC growth and stemness. We utilized single-cell RNA sequencing (scRNA-seq) data for OSCC and normal samples from Gene Expression Omnibus (GEO) to characterize TAM CS polarization and screen critical regulatory molecules. To independently validate the expression of key candidate genes, we additionally analyzed three independent bulk transcriptomics cohorts from GEO, comprising 330 patient tissue samples. A METTL14-overexpressing TAM model was constructed to explore the effects of METTL14 on CS polarization and OSCC growth and stemness. The target gene of METTL14-mediated m6A modification was identified using the RM2Target database and validated by cellular experiments. Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), an m6A reader protein, mediates the downstream biological effects of this epigenetic modification. Finally, the impact of METTL14-driven TAM CS polarization on OSCC tumor growth and stemness was verified in vitro and in vivo in a macrophage-specific Mettl14 knockout mouse model. scRNA-seq re-analysis uncovered mutually exclusive CXCL9⁺ and SPP1⁺ TAM populations in OSCC. METTL14 was markedly enriched and co-expressed in CXCL9⁺ TAMs, where it showed a negative correlation with cancer stemness pathways. Independent validation in three bulk transcriptomics cohorts (n = 330) confirmed significant differential expression of CXCL9 and METTL14 between OSCC tumor and normal tissues. In vitro, METTL14 overexpression in TAMs promoted CXCL9⁺ TAM generation and suppressed OSCC cell growth and stemness, an effect attributed to METTL14-mediated m6A modification of CXCL9 mRNA, which was recognized and stabilized by the m6A reader protein IGF2BP3. Consistently, in vivo assays using macrophage-specific METTL14-knockout mice revealed that METTL14 knockdown reduced m6A modification levels of CXCL9 mRNA, promoted the polarization of TAMs toward the SPP1⁺ phenotype, and ultimately accelerated OSCC tumor growth and enhanced cancer stemness. Collectively, this study identifies a novel mechanism wherein METTL14 regulates TAM CS polarization by promoting m6A modification of CXCL9 mRNA, thereby driving TAMs towards a CXCL9⁺ phenotype and suppressing OSCC growth and stemness.

The hypothesis of the glymphatic system as playing an important part in clearing waste from the brain has revolutionized our understanding of cerebrospinal and interstitial fluid dynamics in the brain. This review explores current knowledge of central nervous system (CNS) malignancies and their implications in the glymphatic system function. Here, we synthesize all available preclinical and clinical evidence on glymphatic dynamics in CNS malignancies. The human data evaluated (gliomas, meningiomas, peritumoral edema, and cerebral metastasis) constitute the total scope of current research. We conducted a systematic search in the PubMed database for studies published between 1 January 2015 and 1 January 2026. We selected 22 studies based on their relevance regarding brain tumors and their relationship to glymphatic system dysfunction. In contrast to animal studies that rely on contrast-enhanced imaging, human studies predominantly use the diffusion tensor imaging along perivascular spaces (ALPS) index due to its noninvasive nature and feasibility with multidirectional diffusion-weighted imaging, which is available on most clinical scanners. However, interpretation of the findings remains the subject of debate, particularly regarding the influence of microstructural factors and other parameters on index values. Consequently, current approaches increasingly assess the ALPS index as a potential indirect marker of glymphatic function alongside complementary MR-based techniques, including multiparametric mapping, volumetry, free water estimation, and DTI-derived microstructural measures. Further research in CNS tumors is required to clarify consistent patterns and address the variability of reported findings.

The recent update from the European Society of Cardiology on preclinical models of cancer therapy-related cardiac dysfunction highlights a critical need for more representative and translational in vivo models. It pinpoints the need to develop models that employ immunocompetent, tumor-bearing animals, incorporating multiple strains and both sexes, to more accurately recapitulate the heterogeneity observed in clinical populations. Therefore, a clinically relevant model of anthracycline-induced cardiotoxicity (AIC) in breast tumor-bearing animals was built. According to mice' genetic background, either 4T1Luc-cells (200k cells) or PY8119-cells (200k cells) were injected in Balb/c-mice or C57Bl/6J-mice, respectively subcutaneously in the lower mammary gland of males and females. Tumor growth was controlled with bioluminescence and palpation. Once the tumor mass was detectable by palpation, 2 weeks post-tumor cell injection, animals received anticancer Doxorubicin treatment. Mice's tolerance to Doxorubicin was strain-dependent. Cardiac function was evaluated before the start of the protocol (baseline) and weekly after by cardiac ultrasound in ketamine-anesthetized mice. Cardiotoxicity was defined as a decrease in left ventricular fractional shortening of at least 10% from baseline, an absolute value <50%, and a heart rate >300 BPM. The protocol was reproducible with a 99% success of tumor development, and a >80% mice survival rate. Cardiotoxicity was observed in >90% of the treated mice with tumor and Doxorubicin.

This systematic review and meta-analysis evaluated the efficacy and safety of Xiaoaiping Injection (XAP) combined with chemotherapy versus chemotherapy alone in patients with breast cancer and aimed to provide an evidence-based reference for clinical treatment. PubMed, Embase, Web of Science, the Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Data, and the China Biomedical Literature Database (CBM) were searched from inception to April 30, 2025, for studies on breast cancer. Pairwise meta-analyses were performed using Stata 17.0 and RevMan 5.4.1. A total of eight studies were included. Pooled analysis indicated that, compared with chemotherapy alone, Xiaoaiping Injection combined with chemotherapy significantly improved outcomes in patients with breast cancer (P < 0.05), reduced the incidence of chemotherapy-induced adverse effects [RR = 0.67, 95% CI (0.54, 0.82), Z = 3.79, P = 0.0002], and increased the objective response rate [RR = 1.37, 95% CI (1.21, 1.55), Z = 5.11, P < 0.00001]. Thus, Xiaoaiping Injection combined with chemotherapy was more effective than chemotherapy alone for breast cancer, reducing the incidence of gastrointestinal adverse reactions and improving the objective response rate. Nevertheless, further studies are needed to provide more robust supporting evidence.

Glomus tumors are benign neoplasms arising from the glomus body. They commonly occur in the distal fingers and subungual region and typically present with severe localized paroxysmal pain, point tenderness, and cold sensitivity. Although the lesions are small, they can cause long-standing and marked pain. An adult woman presented in 2018 with localized pain in the pulp of the left ring finger. Ultrasonography and contrast-enhanced MRI identified a small lesion, which was surgically excised and histopathologically confirmed as a glomus tumor. Importantly, the same magnetic resonance imaging (MRI) examination also demonstrated a separate enhancing lesion in the distal left index finger, although this lesion was clinically asymptomatic at that time. Approximately seven years later, the patient developed localized pain in the distal index finger. Repeat MRI demonstrated a lesion in the same anatomical region, and surgical excision followed by histopathological examination again confirmed a glomus tumor. These findings support synchronous glomus tumors in different fingers, with delayed symptomatic presentation of the index-finger lesion. In patients with well-localized and recurrent digital pain, even when there is a history of glomus tumor, diagnosis and management should follow the principle of relocalizing a new lesion. Combined assessment with ultrasonography and contrast-enhanced MRI may improve the localization accuracy of small lesions and guide surgical strategy.

Ras-related protein Rab-27A (RAB27A) is involved in tumour progression and immune regulation. This study investigated its role in triple-negative breast cancer (TNBC) progression, immune escape and responsiveness to immune checkpoint inhibitors. RAB27A expression was analysed in TNBC tissues and public datasets. Gain- and loss-of-function experiments were performed in TNBC cells. Peripheral blood mononuclear cell (PBMC)-based tumour coculture systems and xenograft mouse models were used to evaluate antitumor immunity and therapeutic responses. RAB27A was upregulated in TNBC and correlated with chemotherapy resistance, advanced T stage, high Ki-67 expression and CD8⁺ T-cell infiltration. RAB27A overexpression activated PI3K/Akt/mTOR signalling and promoted tumour cell migration and invasion, whereas RAB27A silencing had the opposite effects. Combined RAB27A targeting and PI3K inhibition decreased PD-L1 expression and cell viability while increasing HLA-I expression and apoptosis; these effects were further enhanced by pembrolizumab. In PBMC coculture models, combination treatment promoted T-cell proliferation and CD8⁺ T-cell expansion while suppressing malignant phenotypes. In vivo, RAB27A knockdown inhibited tumour growth, reduced PI3K/Akt/mTOR activation and PD-L1 expression and increased HLA-I expression. Targeting RAB27A enhances antitumor immunity and pembrolizumab sensitivity by blocking the PI3K/Akt/mTOR axis, representing a potential strategy to overcome immune resistance in TNBC.