Interleukin-10 (IL-10) is classically defined as a potent anti-inflammatory cytokine that protects tissues by constraining myeloid activation and limiting inflammatory cytokine production. Yet, accumulating evidence indicates that, in defined contexts, IL-10 can also promote antitumor immunity by enhancing the fitness and cytotoxic programs of CD8⁺ T cells and natural killer (NK) cells. Conversely, in other tumor contexts, IL-10 may reinforce immunosuppressive myeloid and regulatory programs, and the factors that determine these divergent outcomes remain incompletely understood. Although these effects converge on a common JAK1/TYK2-STAT3 signaling hub, the downstream biological outcomes are combinatorially shaped by the identity, activation, and chromatin state of the responding cell, co-engaged pathways, including STAT1, mTORC1, and NF-κB/AP, receptor abundance, feedback regulation, and the surrounding microenvironment. Recent studies suggest IL-10 can sustain cytotoxic lymphocyte function under tumor microenvironmental stress through effector programming, restraint of terminal exhaustion, mitochondrial metabolic reprogramming, and remodeling of the tumor microenvironment (TME). However, several of these mechanisms remain supported primarily by limited preclinical models and correlative human data. These advances have promoted the development of pharmacokinetically optimized IL-10 variants, tumor-targeted immunocytokines, surrogate bispecific IL-10 receptor agonists, and IL-10-armored adoptive cell therapies. Although several approaches have shown immune activation and preliminary antitumor activity in early-phase studies, pegilodecakin-the only IL-10-based agent to complete a randomized phase III oncology trial-did not improve survival in gemcitabine-refractory pancreatic cancer, underscoring the gap between pharmacodynamic activity and established clinical benefit. In this review, we synthesize mechanistic and translational advances with conflicting and cautionary evidence, discuss safety considerations associated with IL-10-based agents and IL-10-armored cell therapies, and propose a context-dependent framework for their further development based on tumor and microenvironmental features, spatiotemporal control, rational combination strategies, and candidate biomarkers.

Immune cell-derived exosomes are important mediators of intercellular communication within the tumor microenvironment. Their biological effects are influenced by the immune-cell source and activation state, vesicular cargo, recipient-cell type, and tumor context. This review examines immune cell-derived exosomes as bidirectional regulators of cancer-associated signaling, with emphasis on their antitumor and protumor mechanisms rather than classification by parent cell type alone. Antitumor exosomes can enhance antigen presentation, activate natural killer cell and T-cell responses, reprogram tumor-associated macrophages, reduce immune-checkpoint signaling, induce tumor-cell death, and suppress tumor growth and metastasis. Conversely, exosomes released by regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and other immune populations may promote immune suppression, tolerogenic reprogramming, checkpoint-mediated immune escape, invasion, metastasis, and treatment resistance. These effects are mediated through the transfer of proteins, receptors, enzymes, cytokine-related molecules, microRNAs, long non-coding RNAs, and other regulatory cargo that modulate signaling networks such as NF-κB, MAPK/ERK, PI3K-AKT-mTOR, STAT3, PD-1/PD-L1, apoptotic, and β-catenin/HIF-1α-associated pathways. Despite their therapeutic and diagnostic potential, clinical translation remains limited by extracellular-vesicle heterogeneity, incomplete identification of functional cargo, inconsistent isolation and characterization methods, manufacturing challenges, storage instability, and difficulties in tracking vesicles in vivo. Future studies should aim to define the relationships among parent-cell state, exosomal cargo, recipient-cell identity, and downstream biological responses. Additionally, integrating experimental data with computational and artificial-intelligence-based approaches may support single-vesicle classification, inference of EV cellular origin, and the development of more reproducible exosome-based cancer therapies.

Gastric cancer (GC) is characterized by marked heterogeneity and frequent resistance to chemotherapy and immunotherapy. Exosomes mediate intercellular communication between tumor, stromal, and immune cells and may couple metabolic adaptation to immune suppression. This review synthesizes evidence for a bidirectional exosome-mediated metabolic-immune axis in GC. Tumor-derived exosomes enhance glycolytic and other metabolic programs, remodel macrophage and lymphocyte function, and promote immune escape, metastasis, and treatment resistance. Conversely, exosomes released by cancer-associated fibroblasts, tumor-associated macrophages, and mesenchymal stromal cells reinforce tumor-cell metabolism, stemness, survival, and chemoresistance. Together, these reciprocal interactions form a self-reinforcing circuit that links metabolic plasticity with an immunosuppressive microenvironment. We further evaluate circulating exosomal cargoes as candidate biomarkers for liquid biopsy and discuss therapeutic approaches involving inhibition of exosome biogenesis or uptake, combined metabolic and immune targeting, and engineered exosome delivery. Finally, we emphasize the limitations imposed by model systems, extracellular-vesicle heterogeneity, incomplete cell-type specificity, and inconsistent isolation and characterization methods. Defining reproducible, subtype-specific exosome-mediated interactions will be essential for translating this framework into clinically useful biomarkers and therapeutic strategies.

Locally advanced head and neck squamous cell carcinoma (LA-HNSCC) remains difficult to treat despite multimodal therapy. Immune checkpoint inhibitors (ICIs) have expanded treatment options, but phase III trials combining ICIs with chemoradiotherapy have demonstrated limited survival benefit due to complex resistance mechanisms. These include immunosuppressive tumor microenvironments, impaired DNA damage responses, hypoxia-driven adaptations, metabolic reprogramming, and oncogenic signaling via the HER receptor family. This review outlines key resistance pathways and emerging strategies to overcome them. Nanotechnology-based approaches may enhance drug delivery and modulate the tumor microenvironment, while dual inhibition of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 3 (HER3), and downstream pathways shows promise in addressing compensatory signaling. Advances in biomarkers, including programmed death-ligand 1 (PD-L1), circulating tumor DNA, metabolic profiling, and radiomics, enable improved patient selection and monitoring. Novel immune checkpoints and adoptive cellular therapies, alongside personalized and adaptive trial designs, offer potential to improve outcomes in LA-HNSCC.

BRAF V600E occurs in selected primary central nervous system (CNS) tumors and in a subset of thyroid cancers that can metastasize to the brain, but the shared alteration does not make these diseases biologically equivalent. This Mini Review examines programmed cell death evasion in pleomorphic xanthoastrocytoma and ganglioglioma, with selected molecular and clinical comparisons involving epithelioid glioblastoma, pilocytic astrocytoma, pediatric low-grade glioma, and thyroid cancer brain metastases (TCBM). Evidence linking BRAF-MEK-ERK signaling to apoptosis is strongest in non-CNS thyroid cancer and other BRAF-mutant models; direct validation in TCBM remains limited. Ferroptosis sensitization has been demonstrated preclinically in BRAF V600E anaplastic thyroid cancer outside the brain, whereas the ferroptosis suppressor protein 1 (FSP1)/coenzyme Q10 (CoQ10) axis and dihydroorotate dehydrogenase (DHODH) remain general mechanistic frameworks rather than established dependencies in the target CNS settings. Clinical studies support BRAF/MEK inhibition in BRAF V600E-mutant glioma and systemic anaplastic thyroid cancer, but direct TCBM intracranial evidence is restricted to very limited, confounded observations. The intact blood-brain barrier, heterogeneous blood-tumor barrier, efflux transporters, and brain microenvironment further complicate inference from systemic outcomes. We therefore separate direct, indirect, and hypothesis-generating evidence and identify disease-specific pharmacokinetic, mechanistic, and prospective clinical studies as priorities.

Peripheral blood mononuclear cell (PBMC) immunophenotyping has emerged as a promising non-invasive approach to characterize systemic immune alterations in cancer and to identify biomarkers associated with treatment response and resistance. However, current evidence remains fragmented and predominantly descriptive, with substantial heterogeneity in study design, immunophenotyping methodologies, and patient populations, limiting the identification of robust and clinically translatable immune signatures. In this review, we aim to comprehensively analyze PBMC immune phenotypes across multiple cancer types, with particular emphasis on their association with disease progression, therapeutic outcomes, and the key methodological and translational challenges that currently limit their clinical implementation. Across malignancies, conserved immune features are consistently observed, including T cell exhaustion, regulatory T cell (Treg) expansion, and upregulation of immune checkpoint molecules, reflecting chronic immune activation and dysfunction. In parallel, tumor-specific phenotype, such as peripheral helper T (Tph) cell expansion in non-small cell lung cancer, Vδ1⁺CD69⁺ γδ T cells in hepatocellular carcinoma, and T-cell immunoreceptor with Ig and ITIM domains (TIGIT) positive dysfunctional T cells in oral squamous cell carcinoma, highlight the influence of tumor-specific immune contexts. Importantly, this review moves beyond descriptive reporting by integrating mechanistic insights into how PBMC phenotypes contribute to therapeutic resistance. Key mechanisms include immunosuppressive cytokine signaling (e.g., interleukin-10 (IL-10), transforming growth factor-β (TGF-β)), chronic antigen stimulation driving T cell dysfunction, and systemic immune-tumor crosstalk mediated by chemokine axes such as stromal cell-derived factor 1 (SDF-1)/C-X-C motif chemokine receptor 4 (CXCR4). In addition to lymphoid populations, we emphasize the contribution of myeloid cell subsets, including monocytes and myeloid-derived suppressor cells, as central regulators of immune evasion and treatment failure. Despite these advances, significant challenges remain, including the lack of standardized protocols, limited longitudinal and multicenter validation studies, and insufficient integration of multi-omics approaches. Addressing these limitations will be essential for clinical translation. Overall, this review provides a refined conceptual framework that distinguishes conserved and tumor-specific immune signatures and highlights their mechanistic relevance in therapeutic resistance, supporting the development of PBMC immunophenotyping as a tool for personalized cancer immunotherapy.

Background: Fascin actin-bundling protein 1 (FSCN1) modulates the expression of key lipogenic enzymes fatty acid synthase (FASN) and stearoyl-CoA desaturase (SCD1) in colorectal cancer (CRC), but the underlying mechanisms remain elusive. Methods: Bioinformatics analyses were performed to evaluate FSCN1 expression and its prognostic value in CRC. Intracellular lipid levels following FSCN1 knockdown were assessed by Nile Red/DAPI co-staining and triglyceride quantification, and further validated by Oil Red O staining of xenograft tumors. Expression levels of key metabolic enzymes were measured by qRT-PCR and Western blotting. RNA sequencing identified FSCN1-associated pathways, which were functionally investigated using pharmacological inhibitors. Results: FSCN1 was significantly upregulated in CRC (p < 0.001; AUC = 0.796) and was correlated with poorer overall survival (p = 0.018). FSCN1 depletion reduced intracellular lipid accumulation, accompanied by downregulation of lipogenic mediators-sterol regulatory element-binding transcription factor 1 (SREBF1; protein product: SREBP1), FASN, and SCD1-and upregulation of peroxisomal fatty acid oxidation (FAO)-related factors-peroxisome proliferator-activated receptor alpha (PPARA; protein product: PPARα) and acyl-CoA oxidase 1 (ACOX1). Mechanistically, FSCN1 was associated with activation of the protein kinase B/mammalian target of rapamycin (AKT/mTOR) and p38 mitogen-activated protein kinase (p38 MAPK) pathways; pharmacological inhibition with LY294002 or SB203580 phenocopied the lipid-lowering effects of FSCN1 knockdown. Conclusion: Collectively, these findings link FSCN1 to the AKT/mTOR/SREBP1/(FASN/SCD1) lipogenic axis and the p38 MAPK/PPARα/ACOX1 peroxisomal FAO pathway, implicating FSCN1 in lipid metabolic regulation and CRC progression, while suggesting a putative functional regulatory axis and a promising candidate therapeutic target for CRC.

Background: Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, with limited treatment options for advanced-stage patients. DNA polymerase theta (POLQ) is overexpressed in various cancers, but its role and underlying mechanisms in CRC remain not fully elucidated. This study aimed to investigate the expression, prognostic value, biological functions, and molecular mechanisms of POLQ in CRC. Methods: POLQ expression was analyzed using public databases and 55 paired clinical samples. Lentivirus-mediated knockdown and overexpression were employed to assess CRC cell proliferation, migration, and invasion. Single-cell transcriptomics and CellChat analysis were used to explore the tumor microenvironment (TME). Western blotting, immunofluorescence, and dual-luciferase reporter assays were performed to verify the Wnt/β-catenin pathway and epithelial-mesenchymal transition (EMT). Results: POLQ was significantly overexpressed in CRC tissues and cell lines, and high POLQ expression was associated with neural invasion, vascular tumor thrombus, lymph node metastasis, advanced TNM stage, and poor prognosis. Single-cell analysis revealed that POLQ was specifically enriched in malignant epithelial cells, which acted as communication hubs with prominent Wnt signaling. Functional experiments demonstrated that POLQ activated the Wnt/β-catenin pathway, induced EMT, promoted β-catenin nuclear translocation and TCF/LEF transcriptional activity, and enhanced CRC cell proliferation, migration, and invasion. The Wnt inhibitor XAV939 reversed the POLQ overexpression-induced malignant phenotype, while the Wnt activator SKL2001 partially rescued the knockdown phenotype. Additionally, single-cell transcriptomics and CellChat analysis generated a computational prediction that POLQ-high cells may be involved in remodeling of the immunosuppressive microenvironment; however, this inference requires direct experimental validation through immune cell profiling in future studies. Conclusions: POLQ promotes CRC progression by activating the Wnt/β-catenin-EMT axis. Bioinformatic inference suggests a potential association with an immunosuppressive microenvironment, but this finding remains correlative and requires experimental confirmation. These findings suggest that POLQ is a potential prognostic biomarker and therapeutic target, though further validation in prospective, multicenter cohorts is warranted.

Breast cancer (BC) has become the most commonly diagnosed malignant tumor among women worldwide, with approximately 70% of patients with advanced BC developing bone metastases. These metastases trigger bone destruction and skeletal-related events (SREs) and significantly reduce patient survival. In recent years, research into the mechanisms underlying BC bone metastasis has advanced rapidly. Molecular biological and genomic studies have revealed that BC bone metastasis is co-regulated by multiple signaling pathways through crosstalk between BC cells and the bone microenvironment. This review analyzes the research progress of signaling pathways involved in BC bone metastasis and systematically elaborates four core cascades: Wingless-related integration site (Wnt)/β-catenin, transforming growth factor-β (TGF-β), RANK/receptor activator of nuclear factor-κB ligand (RANKL)/osteoclastogenesis inhibitory factor (OPG), and phosphatidylinositol 3-Kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR). It explains how each pathway mediates epithelial-mesenchymal transition (EMT), excessive Osteoclast (OC) activation, maintenance of cancer stem cell stemness, and the formation of an immunosuppressive microenvironment. The positive feedback loops and reciprocal crosstalk between these pathways are also summarized, which together fuel the vicious cycle of osteolytic bone metastasis. This paper further consolidates therapeutic strategies targeting the aforementioned signaling pathways and outlines cutting-edge therapeutic approaches and emerging research hotspots. Nevertheless, critical obstacles including complex pathway compensation, drug resistance, and dysregulated bone immunity remain major bottlenecks hindering clinical translation. Future research will leverage single-cell sequencing and multi-omics technologies to identify pivotal molecular targets and develop potent combinatorial therapies. Such advances will facilitate the implementation of precise, individualized treatment for BC bone metastasis and ultimately improve the quality of life and long-term clinical outcomes of patients with advanced bone-metastatic disease.

Chronic lymphocytic leukemia (CLL) is a biologically heterogeneous B cell malignancy in which non-malignant T lymphocytes constitute a critical component of the tumor microenvironment and significantly influence disease evolution and the therapeutic response. Growing evidence suggests that CLL-associated T cells not only participate in the antitumor response but also activate signals that promote the development of CLL subclones. Although novel targeted therapies, such as Bruton's tyrosine kinase (BTK) inhibitors, BTK degraders, B-cell lymphoma 2 (BCL-2) inhibitors, T cell engagers, immune checkpoint inhibitors, and adoptive T cell therapy have different mechanisms of action, they affect the T cell compartment in addition to targeting CLL cells. Therefore, in-depth knowledge of the role of T cells in the development and progression of CLL is essential for proper stratification of the benefit-to-risk ratio with regard to immunotherapeutic strategies. This review comprehensively summarizes current knowledge on alterations within the T cell compartment in CLL and discusses the clinical implications, regarding clinical course and response to immunotherapy.