Cancer Biology & Medicine最新文献

Objective: Conventional tumor-infiltrating lymphocyte (TIL) therapy for solid tumors relies on high-dose interleukin-2 (IL-2) during expansion and post-infusion, and promotes T-cell exhaustion and toxicity. Herein, we developed a feeder-free, low-dose IL-2 TIL expansion protocol and evaluated whether hydroxychloroquine (HCQ) or programmed cell death protein 1 (PD-1) blockade might enhance therapeutic efficacy and decrease IL-2 dependence.

Methods: TILs from multiple solid tumors were expanded ex vivo with decreased-dose IL-2, IL-7, and IL-15 plus CD3/CD28 co-stimulation, without feeder cells. TIL products were assessed via quality control, T-cell phenotypes, and exhaustion markers. Cytotoxic activity was measured in vitro through interferon-gamma (IFN-γ) release and real-time cell analysis (RTCA). HCQ-induced changes in major histocompatibility complex class I (MHC-I) and programmed death-ligand 1 (PD-L1) expression were assessed in tumor cell lines, and RTCA-based cytotoxicity was evaluated using T-cell receptor-engineered T cells (TCR-T cells). The in vivo efficacy of HCQ and PD-1 blockade separately combined with TIL therapy was examined in a colorectal cancer patient-derived xenograft (PDX) model.

Results: The protocol consistently produced viable TILs of favorable quality across tumor types, with variable CD8⁺ and memory T-cell profiles. Expanded TILs showed effector-to-target (E:T) ratio-dependent tumor cell killing in RTCA and secreted IFN-γ across multiple tumor types. HCQ significantly upregulated MHC-I expression in vitro (P < 0.05) without affecting PD-L1 expression or impairing TIL proliferation, and enhanced early TCR-T-mediated killing. In the PDX model, TIL plus HCQ, compared with TIL, showed less tumor growth and greater MHC-I expression, although these differences were not significant, given the small sample size. TIL plus low-dose PD-1 blockade significantly reduced tumor volume versus the control group (P = 0.002) and maintained higher body weights than the TIL-only and control groups.

Conclusions: The feasibility of a feeder-free, low-dose IL-2 TIL expansion system was demonstrated. PD-1 blockade significantly enhanced antitumor activity and treatment tolerability, thus supporting its promise as an alternative to high-dose IL-2. HCQ demonstrated potential immunomodulatory effects, although its in vivo benefit was minimal. This strategy warrants further clinical evaluation in solid tumors.

Emerging evidence suggests that the efficacy of immunotherapy in patients with advanced HER2-negative gastric cancer differs between Asian and non-Asian populations. This review examines potential factors contributing to these disparities, including differences in demographic and clinicopathologic characteristics, somatic mutations, molecular subtypes, tumor immunity, Helicobacter pylori (H. pylori) infection, dietary habits, and gut microbiome composition. These factors may serve as predictors of immunotherapy response in gastric cancer patients. For example, the prevalence of molecular subtypes and somatic mutations have been linked to variations in immunotherapy efficacy between Asian and non-Asian populations. In addition, differences in H. pylori infection rates, dietary habits, and gut microbiota composition may influence systemic immune responses, and consequently, immunotherapy outcomes. Understanding the factors contributing to these disparities in immunotherapy response is crucial for optimizing treatment strategies and improving outcomes for patients with gastric cancer. Further research into the mechanisms underlying racial and ethnic disparities in immunotherapy response is needed to identify potential biomarkers predictive of immunotherapy response in diverse patient populations.

Objective: Upper gastrointestinal (UGI) cancer, including esophageal and gastric cancers, poses a significant health burden. While unhealthy dietary patterns are a recognized risk factor for UGI cancer, the complex interplay with psychological health that influences UGI cancer risk remains underexplored. The current study aimed to determine the association between dietary quality and UGI cancer, and the link with depression and anxiety symptoms.

Methods: Cross-sectional data were drawn from the baseline survey of the National Cohort of Esophageal Cancer study that was conducted between 2017 and 2019 in five high-risk regions of China. Dietary quality was evaluated using the Diet Balance Index (DBI)-16. Psychological symptoms were measured with the Generalized Anxiety Disorder 7-item Scale (GAD-7) and the Patient Health Questionnaire (PHQ)-9. Eligible participants underwent endoscopy screening and suspicious cases were confirmed via pathologic biopsies.

Results: A total of 434 UGI cancer cases were confirmed among 29,068 participants. Logistic regression models indicated that poor diet quality, reflected by an inadequate intake [low bound score (LBS)] and unbalanced diet [dietary quality distance (DQD)], was associated with psychological distress (e.g., LBS and anxiety: OR = 1.36, 95% CI: 1.19-1.56). UGI cancer participants had more severe psychological symptoms (e.g., anxiety and UGI cancer: OR = 1.20, 95% CI: 1.14-1.26). Path analysis further revealed that psychological symptoms significantly mediate the relationship between poor dietary quality and UGI cancer risk; specifically, anxiety symptoms mediated 27.78% of the LBS-UGI cancer link.

Conclusions: The current study revealed a significant association between dietary quality and UGI cancer risk, suggesting that psychological symptoms may have a mediating role. Incorporating dietary and psychological health management into public health strategies is crucial for comprehensive cancer prevention.

Colorectal cancer (CRC) remains a major global health burden with the gut microbiome emerging as a critical contributor to tumor initiation and progression. Advances in high-throughput sequencing have deepened our understanding of host-microbe interactions across genomic, transcriptomic, epigenomic, and metabolomic levels. This review synthesizes current knowledge on how microbial communities shape colorectal carcinogenesis, including induction of genomic instability, remodeling of host transcriptional and epigenetic landscapes, and reprogramming of metabolic pathways within the tumor microenvironment. Integrative multi-omics strategies and advanced computational tools are powerful means for dissecting these complex biological systems. However, analytical challenges, such as data compositionality, sparsity, and high dimensionality, still hinder meaningful interpretation. Emerging technologies, like long-read sequencing and bacterial single-cell spatial transcriptomics, are enhancing the resolution and accuracy of microbiota profiling. Finally, the convergence of advanced experimental models, artificial intelligence-driven computational integration, and precision microbiome medicine are highlighted as key avenues for translating microbiome insights into preventive, diagnostic, and therapeutic innovations in CRC.

Objective: Intratumoral heterogeneity refers to the presence of distinct subpopulations of cancer cells within a single tumor, which exhibits variations in phenotypic traits, such as proliferation rate, drug sensitivity, and metastatic potential. Dynamic interactions among heterogeneous cell populations have a critical role in tumor progression. Increasing evidence underscores the importance of intercellular communication among heterogeneous cancer cell subpopulations in driving malignancy. However, the molecular mechanisms governing such cancer cell-to-cancer cell interactions are poorly understood.

Methods: Exosomes were isolated from highly metastatic breast cancer cells (HM-BCCs) and low metastatic breast cancer cells (LM-BCCs). The role of exosome-mediated intercellular communication on metastatic behavior was assessed using wound healing and Transwell assays. Gene knockdown and overexpression strategies, small-molecule inhibitors, and xenograft mouse models were used to elucidate the role of exosomal EPHA2.

Results: Exosomes derived from HM-BCCs considerably enhanced the migratory and invasive capabilities of LM-BCCs in vitro and increased the metastatic potential in vivo. Mechanistically, EPHA2 was identified as a key protein enriched in exosomes from HM-BCCs and was shown to be transferred to LM-BCCs by these vesicles. Exosomal EPHA2 promoted epithelial-to-mesenchymal transition in LM-BCCs when internalized by stabilizing TGF-βRI and activating the transforming growth factor-β/mothers against decapentaplegic homolog 3 (TGF-β/SMAD3) signaling pathway, thereby facilitating the acquisition of a metastatic phenotype.

Conclusions: The results underscore the pivotal function of exosomal EPHA2 in mediating the transfer of metastatic potential among heterogeneous breast cancer cell populations. Targeting the EPHA2-TGF-βRI signaling axis may provide a novel therapeutic approach for preventing or limiting breast cancer metastasis.

Postbiotics, considered the functional successors of live probiotics, retain most of probiotics' structural and/or bioactive properties, and are key mediators of probiotic-environment interactions. Beyond influencing tumor proliferation, metastasis, and immune regulation, postbiotics can enhance the effectiveness of current anti-cancer treatments. Postbiotic-based cancer therapy represents an advanced evolution of bacterial treatment with improved safety and treatment potential. However, the field is limited by postbiotics' imprecise definition and lack of standardized manufacturing methods, which together hinder their clinical application. Here, we establish a systematic classification of postbiotics based on their formation processes, focusing on the complex mechanisms underlying their activity in anti-tumor therapy, their therapeutic promise, and their current clinical use and challenges. Our aim is to guide future research, translation, and industrial development.

Objective: Progressive metabolic adaptation of tumor cells enables a thriving tumor microenvironment in which immune cells have diminished killing ability. However, whether and how this adaptation plays an active role in lymph node (LN) metastasis of lung cancer remains unclear.

Methods: We collected 37 matched samples of primary tumors, metastatic LNs (MetLNs), uninvolved LNs (uiLNs), and peripheral blood from 10 patients with lung cancer. These samples were profiled with single-cell RNA sequencing, T cell receptor/B cell receptor (TCR/BCR) sequencing, and spatial transcriptomics, capturing 671,467 cells in total. Modulator of Cytochrome C Oxidase during Inflammation (MOCCI)-dependent enhancement of oxidative phosphorylation (OXPHOS) and LN metastasis was demonstrated in vivo and in vitro, and its association with adverse prognosis was validated in an independent cohort from Fudan University Shanghai Cancer Center (n = 875). Spatial neighborhood and ligand-receptor analyses were used to examine primary LN metastatic cancer cell (PLMC)-immune interactions.

Results: A PLMC subpopulation, characterized by MOCCI-driven OXPHOS reprogramming, was identified. MOCCI increased OXPHOS and promoted LN metastasis in vivo and in vitro, and higher MOCCI levels correlated with poorer prognosis in the cohort. In MetLNs, follicular helper T cells (Tfh) were significantly elevated but exhibited dysfunctional antigen-presentation programs, whereas naïve and memory B cells were enriched yet showed greater clonal diversity with blunted clonal expansion. Spatial analyses linked these features to MOCCI⁺ PLMCs, which, via GDF15-TGFBR2 axis signaling, drive Tfh exhaustion and suppress adjacent B-cell activation.

Conclusions: This study delineated transcriptional differences between primary tumors and MetLNs in lung cancer, thereby providing a foundation for further exploration of LN metastasis.

Objective: Paclitaxel (PTX), a conventional second-line therapeutic agent for advanced gastric cancer (GC), exhibits compromised clinical efficacy due to acquired chemoresistance in patients, the molecular mechanisms of which remain poorly elucidated. This study aimed to investigate the therapeutic potential of targeting extracellular vesicle (EV) protein in reversing PTX resistance in GC cells and to delineate the underlying molecular pathways involved.

Methods: Proteomic profiling was used to identify differentially expressed EV proteins in PTX-resistant GC cells. EVs were isolated via size exclusion chromatography (SEC) and characterized using transmission electron microscopy (TEM), nano-flow cytometry (nano-FCM), and western blot analysis. In vivo functional validation was performed in xenograft tumor models by injecting EV proteins into nude mice via the tail vein (6 groups, n = 4). EVs derived from 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS)-treated cells were administered to tumor-bearing nude mouse model (4 groups, n = 5) to determine the impact of EV-derived voltage-dependent anion channel protein 1 (VDAC1) on PTX resistance. In addition, VDAC1 protein expression was evaluated using immunohistochemical (IHC) assays in 34 clinical specimens from PTX-resistant patients.

Results: Proteomic analyses demonstrated a marked upregulation of VDAC1 in EVs secreted by PTX-resistant GC cells. Functional studies revealed that intercellular transfer of EV-derived VDAC1 directly conferred PTX resistance to drug-sensitive cancer cells. Gene set enrichment analysis (GSEA) and adenosine triphosphate (ATP) functional assay further elucidated that VDAC1-mediated chemoresistance was mechanistically linked to the activation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signaling and concomitant suppression of the mammalian target of rapamycin - p70 ribosomal protein S6 kinase (mTOR-p70S6K) pathway. In vivo validation confirmed that systemic delivery of EV-derived VDAC1 significantly reduced PTX sensitivity in GC tumors. Furthermore, DIDS inhibited the expression of the VDAC1 protein in EVs, thereby reducing PTX resistance in vivo and in vitro. IHC analysis revealed that VDAC1 expression was significantly higher in GC patients with PTX resistance compared to PTX-sensitive patients.

Conclusions: The findings herein underscore the pivotal role of EV-derived VDAC1 in driving PTX resistance in GC through dual modulation of autophagy and mitophagy, mediated by the AMPK/mTOR signaling axis. Targeting EV-derived VDAC1 has emerged as a promising therapeutic strategy to counteract chemoresistance, providing a novel avenue for improving GC treatment outcomes.

In the past decade, cancer immunotherapy has emerged as a transformative treatment modality for diverse malignancies. Although impressive clinical efficacy has been demonstrated in some cancer patients, most patients respond poorly to immunotherapies. The complicated architecture and cellular composition of the tumor immune microenvironment (TIME) have substantial roles in the clinical outcomes of immunotherapies. Therefore, employing optimal in vitro models recapitulating the in vivo TIME characteristics is particularly important for interpreting the dynamic complexity of the TIME, evaluating drug efficacy, and developing novel immunotherapeutics. In recent years, microfluidic technology has been shown to be a valuable tool for mimicking dynamic crosstalk among the TIME in vitro through the manipulation of microscale fluids in an integrated device. Cellular behaviors, function and signal transduction, and tumor-immune interactions can be monitored in real time and analyzed in microfluidic chips by combining visualization technologies. Numerous recent studies have shown how to design and fabricate microfluidic chips for reproducing the complex three-dimensional architecture and dynamic changes in the TIME. This review comprehensively examines the application of innovative microfluidic technology in the field of cancer immunology research, focusing on interpreting dynamic crosstalk inside the TIME from bulk-cell to single-cell analyses, evaluating the efficacy of novel immunotherapies and preparing immunotherapeutic agents, and analyzes current limitations. This work aimed to propose a translational roadmap for leveraging microfluidics in elucidating mechanisms, biomarker discovery, high-throughput drug screening, and personalized immunotherapy development.