HBeAg seroclearance represents a critical milestone in the treatment of HBeAg-positive chronic hepatitis B (CHB), which is closely associated with disease remission, functional cure, and reduced hepatocellular carcinoma risk. As HBeAg is a secreted viral protein associated with active HBV replication, infectivity, and host immune tolerance, its disappearance usually indicates a transition toward improved immune control rather than simple loss of a laboratory marker. This review comprehensively explores the immunological mechanisms underlying HBeAg seroclearance, thoroughly examines its impact on the natural course of CHB and systematically analyzes the regulatory roles of antiviral drug efficacy, host immune status, and viral genotypes in HBeAg clearance. Integrating updated guidelines and evidence-based research, we propose optimized strategies for managing HBeAg-negative CHB, including goal setting, treatment cessation criteria, and long-term monitoring protocols. Our findings emphasize that HBeAg clearance not only signifies virological suppression but also reflects the dynamic equilibrium of host immune responses, thereby providing both theoretical foundation and practical support for achieving functional cure and reducing HCC risk in CHB patients.

Prostate cancer (PCa) remains a leading cause of cancer-related mortality in men, with current treatments often limited by drug resistance and systemic toxicity. Although traditional Chinese medicine components such as Astragaloside IV and polypeptide extract from scorpion venom (PESV) have demonstrated promising antitumor activity, their clinical translation is hampered by poor bioavailability and lack of tumor specificity. To address these limitations, we engineered an E3 aptamer-modified T cell-derived exosomal nanoplatform (EAPE) for the targeted co-delivery of Astragaloside IV and PESV in prostate cancer therapy.

EAPE was constructed and characterized, and its targeting capability, biosafety, and therapeutic performance were evaluated in vitro and in vivo. In vitro, the antitumor efficacy was assessed by proliferation, migration and apoptosis assays, while the immunomodulatory effects were investigated using a co-culture system of LNCaP cells and T lymphocytes. In vivo, the antitumor efficacy and immune activation were examined in prostate cancer xenograft mouse model, with tumor growth inhibition, apoptosis and immune responses measured.

EAPE demonstrated efficient tumor-targeting capability and favorable biosafety profiles both in vitro and in vivo. EAPE demonstrated superior therapeutic efficacy against PCa by inhibiting proliferation and migration of prostate cancer cells and inducing apoptosis, while suppressing immunosuppression and activating antitumor immune response.

This study presents a biologically derived, targeted nanodelivery system that improves the delivery efficiency and therapeutic efficacy of Astragaloside IV and PESV. These findings support the potential of exosome-based nanoplatforms as promising strategies for enhancing the translational application of traditional Chinese medicine-derived therapeutics in prostate cancer.

Tumor hypoxia is a fundamental hallmark of the solid tumor microenvironment (TME) that severely impairs the efficacy of oxygen-dependent treatments, such as photodynamic therapy (PDT), and drives therapeutic resistance. Overcoming this biological barrier is critical for improving clinical outcomes. This review comprehensively summarizes recent advancements in oxygen-modulating nanobiomaterials designed to tame the hypoxic TME and sensitize tumors to multimodal therapies. We systematically evaluate two primary nanomedicine strategies: exogenous oxygen delivery systems (including hemoglobin-based carriers, perfluorocarbons, and metal-organic frameworks) and in situ oxygen-generating catalysts (such as catalase, solid peroxides, and photocatalytic nanomaterials). Furthermore, nanotechnology-driven approaches for vascular normalization and enhancing oxygen diffusion are discussed. By focusing on material design, we elucidate how stimuli-responsive and actively targeted nanocarriers achieve precise, on-demand TME regulation. Crucially, we explore how these oxygen-enhancing platforms synergize with conventional treatments to reverse therapeutic resistance, enabling robust integrated regimens that combine PDT with chemotherapy, photothermal therapy (PTT), and gas therapy. Finally, we outline current translational challenges, such as nanoparticle stability, deep tumor penetration, and biosafety-and provide perspectives on developing intelligent, multifunctional nanomedicines to definitively break the barrier of tumor hypoxia. To provide a forward-looking paradigm, this review uniquely highlights the disruptive integration of artificial intelligence (AI) in nanomedicine design, single-atom catalysts (SACs) for oxygen-independent Type I PDT, and covalent photosensitizers.

Tumor vaccines represent a promising approach for tumor immunotherapy, yet their clinical translation is greatly impeded by cumbersome antigen screening, poor adaptation to tumor heterogeneity, inefficient antigen presentation, and insufficient immune activation. Tumor microenvironment (TME)-responsive smart hydrogels have emerged as advanced platforms for constructing next‑generation whole‑cell tumor vaccines, featuring tunable microstructures, spatiotemporally controlled cargo release, and excellent in situ TME adaptability. These hydrogel‑based vaccines directly employ intact tumor tissues as broad‑spectrum antigen reservoirs, avoiding complex antigen isolation and identification to effectively overcome tumor heterogeneity. Hydrogel‑based vaccines enable stimuli‑responsive sequential release of antigens, adjuvants, and bioactive factors, precisely modulating immune cascades to elicit robust systemic antitumor immunity against tumor growth, invasion, and metastasis. This review systematically summarizes the design principles, fabrication strategies, and immunomodulatory mechanisms of TME‑responsive hydrogel‑based whole‑cell vaccines, highlights their structure-efficacy relationships, and discusses key challenges in clinical translation. Furthermore, this review proposes future directions to guide the rational development of high‑performance immunotherapeutic formulation with strong clinical potential for personalized tumor treatment.

Poorly and undifferentiated colorectal neuroendocrine neoplasms (CR-NENs) are rare and highly aggressive tumors with limited individualized prognostic assessment. Conventional staging systems are insufficient to capture heterogeneity, and dedicated prognostic models for this subgroup remain lacking. This study aimed to develop and internally validate a multivariable prediction model for survival in patients with CR-NENs.

Patients diagnosed with poorly and undifferentiated CR-NENs were identified from the Surveillance, Epidemiology, and End Results (SEER) database spanning 2000-2019. Eligible cases were randomly divided into training and validation cohorts (7:3). Overall survival (OS) and cancer-specific survival (CSS) were defined as study endpoints. Candidate variables including demographic and clinicopathological factors were analyzed using Cox regression to identify independent predictors, which were incorporated into nomograms. Model performance was evaluated by concordance index (C-index), time-dependent receiver operating characteristic (ROC) analysis with area under the curve (AUC), calibration plots, and decision curve analysis (DCA). Patients were stratified into low- and high-risk groups based on predicted risk scores, and Kaplan-Meier survival analysis was performed.

A total of 904 patients were included. The cohort was characterized by a high proportion of advanced disease, with approximately 80% of patients presenting with T3-4 tumors, about 75% having lymph node involvement, and over 40% with distant metastases. Multivariate analysis identified lymph node metastasis and distant metastasis as independent risk factors, while female sex, married status, and surgical treatment were protective factors (all P<0.05). The nomograms demonstrated moderate discriminative ability, with C-indexes of 0.70 [95% confidence interval (CI): 0.67-0.72] for OS and 0.71 (95% CI: 0.68-0.73) for CSS in the training cohort, and comparable performance in the validation cohort. For OS prediction, the 1-, 3-, and 5-year AUC values were 0.76, 0.82, and 0.85 in the training cohort and 0.72, 0.80, and 0.80 in the validation cohort; for CSS prediction, the corresponding AUC values were 0.76, 0.81, and 0.84, and 0.76, 0.86, and 0.88, respectively. Calibration curves showed good agreement, and DCA indicated clinical net benefit. Risk stratification based on the nomograms effectively distinguished patients with significantly different survival outcomes (P<0.001).

We developed and internally validated a SEER-based prediction model for OS and CSS in poorly and undifferentiated CR-NENs. The model may assist in individualized risk stratification, although further external validation is required before clinical application.

We hypothesized that preoperative administration of liposome arsenic trioxide (LATO) would downregulate hypoxia-inducible factor-1α (HIF-1α) in residual tumors following incomplete radiofrequency ablation (iRFA), thereby modulating the tumor microenvironment, suppressing residual tumor proliferation and angiogenesis, and consequently enhancing the antitumor efficacy of programmed death-ligand 1 (PD-L1) blockade.

Using a murine Hepa1-6 hepatocellular carcinoma model subjected to incomplete radiofrequency iRFA, cohorts were stratified based on preoperative LATO administration and postoperative anti-PD-L1 antibody combination therapy, and the indexes such as proliferation and immune infiltration of residual tumor were tested respectively.

After iRFA, residual tumors exhibited significant up-regulation of PCNA, CD31, and HIF-1α compared with the control group (all p < 0.0001). Intravenous infusion of LATO before RFA could significantly decrease the expression of PCNA, CD31 and HIF-1α in the residual tumor, promote the infiltration of immune cells (CD4⁺, CD8⁺) and prolong the survival time of mice. After RFA, combined use of anti-PD-L1 antibody can further reduce the expression of cell proliferation and tumor proliferation.

Pre-treatment with LATO prior to RFA appears to modulate the tumor microenvironment, which may contribute to improved ablation efficacy and help restrain the progression of residual tumors. Furthermore, it could potentially enhance the antitumor effect of combining RFA with anti-PD-L1 antibody therapy by sensitizing the tumor immune response.

Fusobacterium nucleatum (Fn) is recognized as a novel oncogenic organism closely correlated with colorectal cancer (CRC). Fn can induce gut dysbiosis and promote tumorigenesis through various mechanisms, including activation of oncogenic signaling, modulation of the immune microenvironment, metabolic reprogramming, and epigenetic regulation. Although recent technological breakthroughs have yielded high-resolution Fn detection indicators, clinical translation remains compromised by subspecies heterogeneity, emerging taxonomic updates, and non-standardization of diagnostic platforms. This review integrates recent developments regarding Fn pathogenic mechanisms and taxonomic identification in CRC, including genetic heterogeneity analysis at the species and subspecies levels, elucidation of multi-dimensional oncogenic molecular mechanisms, and application of high-resolution detection technologies. Special focus is placed on advancing these findings toward early noninvasive diagnostic markers. Additionally, we discuss the limitations of current studies, technical bottlenecks, and potential directions for future research to pave the way for standardized clinical screening.^C.

Primary intraosseous adenoid cystic carcinoma (PIACC) of the mandible is an exceptionally rare malignancy. While radical surgery and radiotherapy provide locoregional control, managing distant metastases remains challenging due to the lack of standard systemic therapies and the characteristically "cold" immune microenvironment of adenoid cystic carcinoma (ACC). We report the case of a 62-year-old male diagnosed with PIACC of the mandible presenting with synchronous bilateral pulmonary metastases (Stage IVC). Following radical resection and adjuvant radiotherapy, the patient received first-line maintenance with oral S-1, achieving stable disease for 36 months. Upon pulmonary progression, after a brief and poorly tolerated trial of sintilimab plus S-1 and subsequent docetaxel, therapy was optimized to a metronomic combination of the PD-1 inhibitor sintilimab and oral capecitabine. This immuno-metronomic regimen achieved durable disease stabilization exceeding 47 months with minimal toxicity. Upon discontinuing immunotherapy due to financial constraints, rapid disease progression ensued, underscoring the critical role of the combination. The patient subsequently received salvage anlotinib, achieving brief stabilization, but passed away from severe pneumonia, yielding a total overall survival of 101 months (~8.4 years). This case challenges the paradigm that ACC is intrinsically refractory to immunotherapy. We hypothesize that systemic interventions, potentially including immunogenic cell death induced by intervening chemotherapy and microenvironment remodeling by fluoropyrimidines, may sensitize ACC to PD-1 blockade. While limited by the lack of archival tissue for translational validation, this hypothesis-generating case warrants further investigation into combination immunotherapy strategies for metastatic ACC.

Immunotherapy has emerged as a promising strategy for pancreatic cancer. Radiotherapy not only mediates direct tumor cell killing but also provides a source of tumor antigens for dendritic cells (DCs) uptake and presentation via the induction of immunogenic cell death (ICD). However, the limited antigen presentation efficiency following radiotherapy and the rapid enzymatic degradation of adjuvants within the tumor microenvironment hinder the subsequent efficacy of immunotherapy.

We developed an in situ hydrogel vaccine, Gel-FOLactis. Combined with 8Gy radiotherapy for treatment. This in situ vaccine employs a thermosensitive P407 hydrogel to encapsulate engineered Lactococcus lactis (FOLactis), enabling sustained intratumoral delivery of the immune-stimulating cytokines Fms-like tyrosine kinase 3 ligand (Flt3L) and co-stimulator OX40 ligand (OX40L).

The sustained release of Flt3L recruits and expands conventional type 1 dendritic cells, enhancing their antigen presentation capability for radiotherapy-released antigens. Concurrently, OX40L promotes the activation of tumor-infiltrating effector T cells. This synergy efficiently initiates a potent antigen-specific immune response, leading to improved tumor eradication.

The combined therapy of RH-FOLactis significantly enhanced the anti-tumor immune response and successfully transformed the immunosuppressive tumor microenvironment in pancreatic cancer from "cold" to "hot". These findings highlight the potential of RH-FOLactis as a novel and effective treatment strategy.

Non-alcoholic fatty liver disease (NAFLD) affects over 30% of the global adult population and has been increasingly recognized as an adverse prognostic factor for colorectal cancer (CRC) liver metastasis (CRLM). However, the underlying immune mechanisms remain incompletely understood. This review provides a comprehensive synthesis of how NAFLD-induced lipotoxicity reshapes the hepatic immune microenvironment to create a "fertile soil" for CRC metastatic colonization. We delineate a hierarchical immunosuppressive network involving: (1) lipotoxic apoptosis of CD4+ T cells, depleting the helper T cell pool; (2) expansion and functional reinforcement of regulatory T cells (Tregs) through multiple mechanisms (IL-10/TGF-β/IL-35, CD25-mediated IL-2 competition, CTLA-4 engagement, and granzyme B/perforin production); (3) M2 polarization of tumor-associated macrophages; and (4) recruitment of myeloid-derived suppressor cells (MDSCs) via the CXCL5/CXCR2 axis, which suppress CD8+ T cell function. These processes collectively promote CD8+ T cell exhaustion (marked by PD-1, LAG-3, TIM-3 upregulation) and spatial mismatch with metastatic foci. Importantly, we discuss the emerging evidence linking NAFLD-driven immune dysregulation to reduced responsiveness to immune checkpoint inhibitors, while acknowledging the current limitations in direct clinical validation. By integrating mechanistic insights with therapeutic perspectives, this review offers new targets for risk stratification and combination immunotherapy in the growing NAFLD population. Non-alcoholic fatty liver disease.