Search Results (2,216)

Chimeric antigen receptor (CAR) T cell therapy has demonstrated clinical success in hematologic malignancies but has limited efficacy in solid tumors due to tumor microenvironment (TME) barriers that impede CAR T cell recognition, infiltration, and sustained function. Traditional 2D assays inadequately recapitulate these constraints, necessitating improved in vitro models. This study validated a 3D tumor spheroid platform using an agarose microwell system to generate uniform B7-H3-positive spheroids from multiple solid tumor cell lines, enabling the evaluation of CAR T cell activity. TME-relevant immune modulation under 3D conditions was analyzed by flow cytometry for B7-H3, MHC I/II, and antigen processing machinery (APM), followed by co-culture with B7-H3 CAR T cells to assess cytotoxicity, spheroid integrity, tumor viability, and CAR T cell activation, exhaustion, and cytokine production. Two human cancer-cell-line-derived spheroids, DU 145 (prostate cancer) and SUM159 (breast cancer), retained B7-H3 expression, while MC38 (mouse colon cancer)-derived spheroids served as a B7-H3 negative control. Under 3D culture conditions, DU 145 and SUM159 spheroids acquire TME-like immune evasion characteristics and specifically downregulated MHC-I and APM (TAP1, TAP2, LMP7) with concurrent upregulation of MHC-II and calreticulin. Co-culture showed effective spheroid infiltration, cytotoxicity, and structural disruption, with infiltrating CAR T cells displaying higher CD4⁺ fraction, activation, exhaustion, effector/terminal differentiation, and IFN-γ/TNF-α production. This 3D platform recapitulates critical TME constraints and provides a cost-effective, feasible preclinical tool to assess CAR T therapies beyond conventional 2D assays. Full article

Background/Objectives: To improve the response rate of immune checkpoint inhibitors (ICIs), inducing immunogenic cell death (ICD) is a promising approach. Photothermal therapy (PTT) induces immunogenic cell death and activates anti-tumor immunity. While there are various ICD inducers, the difference in ICD induction by various modalities is poorly understood. In this study, we found previously unrecognized advantages of PTT compared to anti-cancer drugs and showed the usefulness of PTT as an anti-cancer drug-free approach to be combined with immunotherapy. Methods: Gold nanorods were synthesized as photothermal agents and added to culture medium or locally administered to tumor tissues. Mitoxantrone (MIT), an ICD inducer, and cisplatin (CDDP), a non-ICD inducer, were compared with PTT. To assess the induction of ICD, the subcellular localization and amounts of high mobility group box 1 (HMGB1) and calreticulin (CRT) were observed using immunofluorescent staining. FM3A tumor-bearing mice were treated with PTT or anti-cancer drugs, and cell death and DAMPs localization in tumor tissues were analyzed. Also, the supra-additive effect of PTT on ICI was observed. Tumor-infiltrating CD8⁺ T cells were examined to evaluate the immune status in tumor tissues. Results: In vivo assays showed that PTT induces HMGB1 release and increased expression of CRT on the cell membrane. Moreover, PTT showed a supra-additive effect in terms of therapeutic effect and anti-tumor activation when combined with an immune checkpoint inhibitor. Conclusions: In this study, we demonstrated that PTT induced ICD-related signaling and improved the response rate of ICI, which means PTT is a promising combination therapy with ICI. Full article

Prostate cancer (PCa) is the leading cause of cancer-related deaths worldwide and the second most common cancer among men. Treatment options depend on factors like age, androgen sensitivity, PSA levels, Gleason score, TNM stage, and recurrence risk. Available treatments include hormonal therapy, radiation, surgery, and chemotherapy. Early immunological treatments were limited by poor lymphocyte infiltration and an immunosuppressive environment. Today, strategies such as dendritic cell vaccines, immune checkpoint inhibitors (ICIs), and adoptive cell therapy (ACT) are used. ACT, especially CAR T-cell strategies, aims to overcome traditional treatment limitations, particularly in advanced and metastatic castration-resistant prostate cancer (mCRPC), though it remains in early development. Personalized medicine uses molecular insights from the diseased tissue to tailor treatments. Variability in patient response, due to tumor heterogeneity and prior treatments, highlights the importance of personalized and combination therapies as future strategies for effective immunotherapy. This review explores the current landscape of PCa. We analyze treatment guidelines established by NCCN and EANM-ESTRO-ESUR-ISUP-SIOG. We comprehensively examine immunotherapeutic strategies currently available or under investigation for prostate cancer, with particular emphasis on ICIs, ACT with a focus on CAR T-cell therapy, combination approaches and therapeutic synergies, and predictive biomarkers of immunotherapy response. Additionally, we discuss the challenges and future directions in the implementation of immunotherapy for the management of prostate cancer. Full article

Metastatic uveal melanoma (MUM) remains largely refractory to immune-checkpoint inhibition, so recent research has turned to bispecific T-cell engagers (BTCEs), adoptive-cell therapies (ACTs), and oncolytic viruses (OVs). To summarize the available clinical evidence, we performed a structured literature search across PubMed, Scopus, and Europe PMC for primary studies published between 1 January 2010 and 31 May 2025 that enrolled at least three adults with MUM, treated with one of these modalities, and that reported efficacy or grade-3+ safety outcomes; two reviewers independently performed screening, data extraction, and risk-of-bias assessment, and because of notable heterogeneity, we synthesized the findings narratively. Twenty-two studies met the criteria—thirteen phase I–III trials, eight observational cohorts, and one case series—covering fifteen BTCE cohorts, four ACT cohorts, and three OV cohorts. Tebentafusp, the dominant BTCE evaluated in roughly 1150 HLA-A*02:01-positive patients, extended median overall survival from 16.0 to 21.7 months (hazard ratio 0.51, with three-year follow-up HR 0.68) in its pivotal phase-III trial despite objective response rates of only 5–12%, with early skin rash and week-12 circulating-tumor-DNA clearance emerging as consistent markers of benefit. Tumor-infiltrating lymphocyte therapy, administered to about thirty patients, produced objective responses in 11–35% and occasional durable complete remissions, although median progression-free survival remained 2–6 months and severe cytopenias were universal. Three early-phase OV studies, totaling twenty-nine patients, yielded no radiographic responses but showed tumor-specific T-cell expansion and transient disease stabilization. Safety profiles reflected the mechanism of action: tebentafusp most often caused rash, pyrexia, and usually manageable cytokine-release syndrome with grade-3+ events in 40–70% yet discontinuation in roughly 2%; TIL therapy toxicity was driven by lymphodepleting chemotherapy and high-dose interleukin-2 with one treatment-related death; and OVs were generally well tolerated with no more than 20% grade-3 events. Full article

Background: Ovarian cancer remains the deadliest gynecologic malignancy, with its progression closely tied to age-associated remodeling of the tumor immune microenvironment. The laying hen serves as a valuable spontaneous model for human ovarian cancer. Its single-cell analyses may provide valuable insights into the immune-related axis linking ovarian aging to carcinogenesis. Methods: This study applied single-cell RNA sequencing to profile ovaries from three laying hen groups, including 35-week-old normal ovaries (A35w), 110-week-old normal ovaries (B110w), and 110-week-old ovarian cancer tissues (C110w). Key analyses had UCell-based scoring of senescence-related pathways and cancer hallmarks, differential expression analysis for overlapping dysregulated genes, LASSO regression-based prognostic model construction, and assessment of chemotherapy sensitivity and immune infiltration. Results: A comprehensive cellular landscape of chicken ovaries was established, identifying major immune populations including B cells, CD4+ T cells, CD8+ T cells, macrophages, and plasma cells. Senescence-related pathways and cancer hallmarks showed progressive activation in immune cells from A35w to B110w to C110w. A total of 216 genes commonly dysregulated in aging and carcinogenesis, reveal core links between immune dysfunction and malignant transformation. The 20-gene prognostic model derived from these genes stratified human ovarian cancer patients into high-risk and low-risk groups with significant overall survival differences, exhibited robust predictive performance across TCGA, GSE32063, and GSE140082. The model also predicted the differential chemotherapy sensitivity in high-risk and low-risk patients and correlated with specific immune infiltration patterns in the tumor microenvironment. Conclusions: Notably, this is the first single-cell RNA sequencing study of chicken ovarian cancer, and we constructed the 20-gene prognostic model for human ovarian cancer using 216 genes that change significantly in immune cells during both ovarian aging and carcinogenesis. This work provides support to establish the hen as a potential preclinical animal model and a translational tool to guide personalized therapy. Full article

Cutaneous squamous cell carcinoma (cSCC) is an immunogenic malignancy with variable immune infiltration and inconsistent responses to checkpoint blockade. Tumor-infiltrating lymphocytes (TILs) influence tumor progression and therapeutic outcome, yet their phenotypic and functional diversity across disease contexts remains incompletely understood. This review systematically characterizes the TIL landscape in human cSCC. Following PRISMA 2020 guidelines, PubMed and Embase were searched up to May 2025 and restricted to studies evaluating tumor-infiltrating lymphocytes in human cSCC, using the modified Newcatle–Ottawa score to assess risk of bias. Data were synthesized qualitatively given methodological heterogeneity. 48 studies met inclusion criteria. cSCCs exhibited dense CD3⁺ infiltrates composed of cytotoxic (CD8⁺GzmB⁺, Ki-67⁺, CD69⁺) and regulatory (FOXP3⁺, CCR4⁺) subsets. Higher CD8⁺ activity correlated with smaller tumors and longer disease-free survival, whereas FOXP3⁺ enrichment and TGF-β2 signaling promoted immune evasion. Immunosuppressed patients demonstrated diminished CD8⁺ density and clonality. Immune modulation with PD-1/PD-L1 blockade, imiquimod, HPV vaccination, or OX40 stimulation enhanced effector function. The cSCC immune microenvironment reflects a balance between cytotoxic and suppressive factors. Harmonizing multimodal immune profiling and integrating spatial context with systemic immune status may advance both prognostic stratification and therapeutic design. Full article

Bone metastases mark a critical and often terminal phase in cancer progression, where disseminated tumor cells (DTCs) manage to infiltrate and exploit the complex microenvironments of the bone marrow. While most current therapies focus on the well-known late-stage “vicious cycle” of osteolysis, they often overlook the earlier stages, namely, tumor cell colonization and dormancy. During these early phases, cancer cells co-opt hematopoietic stem cell (HSC) niches, using them as sanctuaries for long-term survival. In this review, we bring together emerging insights that highlight a trio of underappreciated cellular players in this metastatic takeover: megakaryocytes, erythroid lineage cells, and perivascular stromal subsets. Far from being passive bystanders, these cells actively shape the metastatic niche. For instance, megakaryocytes and platelets go beyond their role in transport; they orchestrate immune evasion and dormancy through mechanisms such as transforming growth factor-β1 (TGF-β1) signaling and the physical shielding of tumor cells. In parallel, we uncover a distinct “erythroid-immune” axis: here, stress-induced CD71⁺ erythroid progenitors suppress T-cell responses via arginase-mediated nutrient depletion and checkpoint engagement, forming a potent metabolic barrier against immune attack. Furthermore, leptin receptor–positive (LepR⁺) perivascular stromal cells emerge as key structural players. These stromal subsets not only act as anchoring points for DTCs but also maintain them in protective vascular zones via CXCL12 chemokine gradients. Altogether, these findings reveal that the metastatic bone marrow niche is not static; it is a highly dynamic, multi-lineage ecosystem. By mapping these intricate cellular interactions, we argue for a paradigm shift: targeting these early and cooperative crosstalk, whether through glycoprotein-A repetitions predominant (GARP) blockade, metabolic reprogramming, or other niche-disruptive strategies, could unlock new therapeutic avenues and prevent metastatic relapse at its root. Full article

Background: Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy where endogenous steroid excess may foster immune evasion. However, whether this hormonal axis directly modulates the antigen presentation machinery remains unclear. Methods: We applied an immunoinformatics approach to the TCGA-ACC cohort (n = 79) to investigate relationships among steroid phenotype, HLA expression, tumor microenvironment (TME), and patient outcome. Key findings were assessed in an independent validation cohort (ENSAT-ACC, n = 44) using C1A/C1B molecular subtypes corresponding to the steroid phenotypes. Results: Stratification by steroid phenotype revealed two distinct immunological profiles. The high steroid production (HSP) phenotype was associated with suppressed HLA expression and a lymphocyte-depleted “cold” TME. In contrast, the low steroid production (LSP) phenotype displayed elevated HLA expression, enriched T-cell infiltration, and upregulation of immune checkpoints (e.g., PDCD1, CTLA4), consistent with an inflamed but exhausted TME. The core signature of HLA downregulation in the HSP-like phenotype (C1A) and the significant survival advantage of the LSP-like phenotype (C1B) were confirmed in the validation cohort, demonstrating biological robustness despite platform and sample size differences. Conclusions: These findings identify the steroid phenotype as a critical regulator of immune escape in ACC. Our results support incorporating this stratification as a biomarker for patient selection, identifying LSP tumors as the subgroup most likely to benefit from immune checkpoint blockade due to their “hot” yet exhausted microenvironment. Full article

The limited ability of the immune system to infiltrate solid tumors, attributed to the immunosuppressive tumor microenvironment (TME), remains a significant challenge in cancer therapy oncolytic adenovirus (OAd) that can directly kill tumor cells in addition to inducing both innate and adaptive immune responses. Therefore, the use of OAd to treat tumors is an appealing approach. In this study, we engineered an OAd armed with a human granulocyte–macrophage colony-stimulating factor (GM-CSF), controlled by the E2F promoter, Ad5/3-E2F-d24-GM-CSF (named OAd-Z1). The antitumor activity of OAd was tested in vitro and in vivo. These findings demonstrated that OAd expressed GM-CSF, replicated effectively in tumor cells, inhibited tumor growth, activated the de novo antitumor response, promoted apoptosis and immunogenic cell death in tumor cells, and increased cytokine and chemokine production both in vitro and in vivo. Additionally, OAd demonstrated an abscopal effect and stimulated T lymphocyte infiltration in vivo. Our findings demonstrate that OAd-Z1 represents promising immunotherapeutic candidates for lung cancer, with the potential to enhance systemic antitumor immunity. Full article

Background/Objectives: Premalignant laryngeal lesions carry a variable risk of malignant transformation to squamous cell carcinoma. Identifying reliable biomarkers that predict malignant transformation could improve patient management and surveillance strategies. The objective of this work is to perform a systematic review of the literature on biomarkers that predict malignant transformation of premalignant laryngeal lesions. Methods: We conducted a systematic review following PRISMA 2020 guidelines. The PubMed, Scopus and Embase databases, and Google Scholar were searched for studies published between January 2011 and November 2025. Studies investigating biomarkers that predict malignant transformation of histopathologically confirmed premalignant laryngeal lesions were included. Risk of bias was assessed using the ROBINS-I tool. Results: From 166 initially identified records, 11 studies met the inclusion criteria, including 730 patients. These studies investigated diverse biomarker categories such as protein markers (cortactin, FAK, NANOG, SOX2, CSPG4), immune markers (tumor-infiltrating lymphocytes, immune gene signatures), microRNAs (miR-183-5p, miR-155-5p, miR-106b-3p), and genetic markers (chromosomal instability, PIK3CA amplification and mutations, FGFR3 mutations). Five studies provided adequate follow-up data on transformation outcomes. Most studies showed a moderate to serious risk of bias primarily due to limited confounder control and incomplete reporting. Conclusions: While several promising biomarker candidates have been identified, the evidence base remains limited due to small sample sizes, heterogeneous methodologies, and inadequate follow-up data. Cortactin/FAK protein expression and immune signatures are the most promising but require validation in larger, well-designed prospective cohorts. Full article

Ovarian cancer (OC), the third most common gynecologic malignancy, is characterized by high mortality largely driven by chemotherapy resistance, leading to recurrence and metastasis. Using transcriptomic data from GSE73935, we constructed a weighted gene co-expression network and identified eight hub genes (IGF1R, CDH2, PDGFRA, CDKN1A, SHC1, SPP1, CAV1 and FGF18) associated with cisplatin resistance, among which CDH2 emerged as the most clinically relevant candidate. CDH2 demonstrated moderate diagnostic potential (AUC = 0.792) and was markedly upregulated in cisplatin-resistant A2780/CP70 cells. Independent validation using clinical single-cell RNA-seq data (GSE211956) confirmed its selective enrichment in resistant tumor cell subpopulations. Gene set enrichment analysis linked elevated CDH2 expression to p53 signaling, DNA replication, nucleotide excision repair, and Toll-like receptor pathways, with qPCR supporting upregulation of key downstream genes in resistant cells. Immune deconvolution further indicated that high CDH2 expression correlated with increased infiltration of NK cells, Tregs, macrophages, and neutrophils, and immunohistochemistry verified CDH2 overexpression in cisplatin-resistant tissues. In addition, virtual screening and drug sensitivity profiling identified several FDA-approved agents with potential relevance to CDH2-associated drug response. These findings indicate that CDH2 may serve as a candidate marker associated with cisplatin response in OC, and its association with immune cell infiltration provides further insight into mechanisms potentially underlying chemoresistance. Full article

BST2 has emerged as a multifunctional molecule that bridges antiviral defense, membrane architecture, and tumor immunity. Originally characterized as an interferon-inducible restriction factor that tethers virions to the plasma membrane, BST2 is now recognized as an oncogenic driver and immunoregulatory hub in diverse malignancies. In cancer, BST2 expression is frequently upregulated through promoter hypomethylation and transcriptional activation. Functionally, BST2 promotes proliferation, epithelial–mesenchymal transition, anoikis resistance, and chemoresistance, whereas its loss sensitizes tumor cells to proteotoxic and metabolic stresses. Beyond tumor cells, BST2 modulates the tumor microenvironment by promoting M2 macrophage infiltration, dendritic cell exhaustion, and natural killer (NK)-cell resistance, thereby contributing to immune evasion. Elevated BST2 expression correlates with poor prognosis in glioblastoma, breast, nasopharyngeal, and pancreatic cancers, and it serves as a circulating biomarker within small extracellular vesicles. In conclusion, BST2 is a dual-function molecule that integrates oncogenic signaling and immune regulation, making it an attractive diagnostic and therapeutic target for hematological and solid tumors. Full article

The manufacturing process contributes significantly to the proliferation, metabolic state, and functional persistence of chimeric antigen receptor (CAR)-T cells. However, how different culture systems regulate CAR-T cell metabolism and thereby influence their long-term antitumor activity remains poorly understood. In this study, we compared dynamic cultivation using a wave bioreactor with static expansion systems (gas-permeable and conventional T-flasks) for the production of CD99-specific CAR-T cells. CAR-T cells expanded by the wave bioreactor exhibited faster proliferation and stronger cytotoxicity during culture. Upon repeated antigen stimulation, they retained these enhanced functional properties and showed the reduced expression of immune checkpoint molecules, preferentially preserved memory-like subsets, and displayed transcriptional features consistent with memory maintenance and exhaustion resistance. Targeted metabolomic profiling revealed enhanced Tricarboxylic Acid (TCA) cycle activity and features consistent with sustained oxidative phosphorylation, supporting mitochondrial-centered metabolic reprogramming. In a Ewing sarcoma xenograft model, wave bioreactor-cultured CAR-T cells showed a greater percentage of memory-like tumor-infiltrating lymphocytes. Collectively, these results indicate that wave bioreactor-based dynamic cultivation promotes mitochondrial metabolic reprogramming, which is characterized by an enhanced TCA cycle and sustained oxidative phosphorylation, thereby sustaining CAR-T cell functionality and providing a robust platform for the manufacturing of potent and durable cellular therapeutics. Full article

Background: Prostate cancer (PCa) is a prevalent malignancy with a rising incidence. Advanced PCa, often resistant to therapy, remains a major clinical challenge, underscoring the need to identify novel molecular drivers. Methods: Utilizing transcriptomic data from the TCGA and GEO databases, we identified APOBEC3C (A3C) as a key candidate through WGCNA, differential expression analysis, and LASSO regression. Its clinical relevance was assessed via Kaplan–Meier survival analysis. Then, we validated A3C expression patterns using immunohistochemistry and Western blot in normal and malignant prostate cell lines. The functional effects of A3C on proliferation, migration, and invasion and mechanisms of such were evaluated through in vitro gain- and loss-of-function assays (CCK-8, Ki67 staining, wound healing, Transwell, Western blot, etc.). Results:A3C was significantly downregulated in PCa, and this low expression strongly correlated with adverse clinicopathological features, including advanced T stage, higher Gleason scores, and worse survival. Bioinformatically, high A3C expression was associated with an activated anti-tumor immune microenvironment, characterized by enhanced CD8+ T cell infiltration, reduced M2 macrophage abundance, and upregulation of the immune checkpoint CD40. In vitro, A3C overexpression effectively suppressed PCa cell proliferation, migration, and invasion, while its knockdown promoted these malignant phenotypes. Mechanistically, A3C enhances the expression of the STING1 and its downstream related molecules Caspase-1, IL-18, and IL-1β; upregulates DNA damage-protective genes (GSTP1 and GPX3); and enhances the expression of cell cycle regulator GAS1. Conclusions: This study establishes A3C as a suppressor in PCa, which impedes tumor progression by regulating key molecules involved in cellular inflammation, cell cycle arrest, and DNA damage response. Full article

MICB-targeting CAR-NK (chimeric antigen receptor-modified natural killer cells) therapy may serve as off-the-shelf immunotherapy. We designed soluble Anti-MICB-scFv blocks tumor immune evasion targeting the MICB antigen, thereby enhancing CAR-NK cytotoxicity while reactivating endogenous immune attacks against malignancies. The Anti-MICB-CAR includes two Anti-MICB-scFv connected by an F2A linker, the CD8 hinge and transmembrane domain, the 4-1BB co-stimulatory domain, the CD3ζ activation domain, and IL-15. The expression efficiency of Anti-MICB-CAR in NK cells was investigated by flow cytometry; ELISA demonstrated that Anti-MICB-CAR-NK secreted free Anti-MICB-scFv and detected IL-15 secretion. Flow cytometry and CCK8 were utilized to study Anti-MICB-CAR-NK on tumor cell viability. The PANC-1 xenograft model was established in order to elucidate the anti-tumor effects of Anti-MICB-CAR-NK in vivo. In vitro investigations have demonstrated that the treatment of tumor cells with Anti-MICB-CAR-NK supernatant + NK cells or Anti-MICB-CAR-NK cells not only significantly increased the cytotoxic activity of tumor cells, but also secreted and produced higher levels of IL-15, IFN-γ, TNF-α, perforin, and granzyme B compared with NK cells. Anti-MICB-CAR-NK cells exhibit strong cytotoxic activity against tumor cells with high MICB expression. In vivo, Anti-MICB-CAR-NK cells exhibited a substantial inhibitory effect on tumor growth. The IHC results reveal that Anti-MICB-CAR-NK cells show a more pronounced ability to infiltrate the tumor. We demonstrated the successful expression of Anti-MICB-CAR in NK cells, which enhances the anti-tumor activity of NK cells both in vitro and in vivo. This stress ligand-targeting approach provides a promising strategy for solid tumors. Full article