Most cancers are fatal and remain challenging to cure due to changes in tumorigenesis and therapeutic resistance. Despite significant advancements in cancer therapy, a substantial proportion of malignancies exhibit resistance to conventional therapies, driven primarily by cancer plasticity and the emergence of multidrug resistance. Recent cancer treatments include cytotoxic chemotherapy, molecular targeted therapy, and immune checkpoint inhibitors. A major hallmark of cancer cells is their ability to develop sophisticated evasion mechanisms that bypass programmed cell death when exposed to anti-cancer drugs. In addition, malignant cells evade the efficacy of anti-cancer drugs by altering cell proliferation, survival, and metastasis. To suppress oncogenic characteristics, necroptosis-based therapies have attracted substantial attention, as they can inhibit tumorigenesis and improve treatment outcomes across many cancer types. Furthermore, an increasing body of research focuses on suppressing tumorigenesis by targeting receptors that are overexpressed in cancer cells. In this review, we elucidate how tumorigenesis is inhibited by regulating the epidermal growth factor receptor (EGFR)-tumor necrosis factor receptor (TNFR) signaling pathway in necroptosis. By delineating the underlying mechanisms of these receptors, we propose that the induction of necroptosis via EGFR and TNFR represents an innovative paradigm for targeted therapy, offering a strategy to enhance clinical outcomes in treatment-resistant cancers.

Soft tissue sarcomas (STSs) are rare and heterogeneous mesenchymal malignancies characterized by diverse molecular profiles and immune landscapes. Although immunotherapy has revolutionized the treatment of specific solid tumors, its efficacy in STSs remains limited and variable across histotypes. This review explores the panorama of biomarkers of immunotherapy sensitiveness in STSs, with particular emphasis on tumor-intrinsic features and on tumor microenvironment (TME) signatures. Current evidence highlights low tumor mutational burden, rare microsatellite instability, heterogeneous antigen expression, and epigenetic suppression of antigen presentation as hallmarks of the immune resistance that is characteristic of many STSs. However, growing evidence underlines TME composition as a major determinant of response to different types of immunotherapy. Indeed, the presence of B-cell-rich tertiary lymphoid structures and certain traits of adaptive immune responses are provenly associated with enhanced sensitivity to immunotherapy and enhanced outcomes. We further discuss emerging strategies aimed at enhancing STS immunogenicity, either by increasing intrinsic tumor immunogenicity or remodeling TME composition and functional profile. Collectively, the available data support a paradigm shift from a sarcoma cell-centered approach toward a multi-compartment TME-including strategy, providing a framework for the development of more effective and personalized immunotherapeutic strategies in STS.

Hypoxia and the evolving concept of pseudohypoxia are critical in driving tumor angiogenesis, contributing to malignancy progression and therapeutic resistance. Angiogenesis, a common feature of many solid tumors, is promoted by hypoxia-induced overexpression of pro-angiogenic factors (e.g., VEGF, FGF) and genetic mutations (e.g., VHL, SDH) that stabilize hypoxia-inducible factors (HIF) even in normal oxygen conditions, a phenomenon known as pseudohypoxia. Recent experimental studies challenge the view that hypoxia universally enhances vessel growth. In certain models, severe oxygen deprivation impairs angiogenesis. Furthermore, tumor-mediated metabolic reprogramming can drive immune evasion via HIF stabilization in immune cells. These paradoxes, together with persistent therapy resistance and the limited effectiveness of current anti-angiogenic treatments, reveal critical gaps in our understanding of how hypoxic signaling modulates vascular and immune dynamics within the tumor microenvironment. These complexities demand more detailed exploration of underlying processes and the development of innovative therapeutic strategies. Here, we review recent mechanistic studies on tumor angiogenesis, summarizing therapeutic and diagnostic advances from both preclinical and clinical studies. We further discuss strategies to exploit hypoxic vulnerabilities, including HIF inhibitors, hypoxia-activated prodrugs, vascular normalization, combination regimens to restore immunity, biomarker-guided patient selection, and advanced hypoxia-targeted imaging to improve outcomes in angiogenesis-driven cancers.

Chronic lymphocytic leukemia (CLL) is characterized by clinical and biological heterogeneity shaped by intrinsic signaling programs and microenvironmental interactions. Established biomarkers, including IGHV mutation status and TP53 alterations, provide important clinical and molecular information, but do not fully capture the diversity of pathways that sustain leukemic cell fitness. Aberrant calcium signaling contributes to leukemic survival; however, the clinical relevance of Ca²⁺/calmodulin-dependent protein kinase kinase 2 (CaMKK2), a calcium-responsive kinase, has not been defined. This study evaluated CaMKK2 as a candidate marker associated with high-risk disease biology and a pathway of interest for further study.

CaMKK2 expression was quantified in purified CD19⁺ CLL cells from a clinically annotated cohort balanced by immunoglobulin heavy chain variable region (IGHV) mutation status. Associations with time to treatment and overall survival were analyzed. Functional relevance was assessed by pharmacologic inhibition of CaMKK2 in primary CLL cells using metabolic (MTS) and apoptosis (Annexin V/PI) assays. Correlations between CaMKK2 expression and inhibitor sensitivity were determined. The impact of CaMKK2 inhibition on nurse-like cell (NLC) differentiation and macrophage-mediated leukemic support was evaluated in ex vivo culture systems.

Elevated CaMKK2 expression was enriched in IGHV-unmutated CLL and associated with shorter time to treatment and inferior overall survival. Pharmacological inhibition of CaMKK2 was associated with reduced primary CLL viability in a dose-dependent manner and increased Annexin V/PI-defined total cell death with sensitivity correlating with CaMKK2 expression levels. Inhibition also attenuated CD163⁺ macrophage polarization and impaired NLC-mediated support of leukemic cells.

CaMKK2 expression is associated with IGHV-unmutated, high-risk CLL biology. Pharmacologic inhibition of CaMKK2 was associated with reduced leukemic cell viability and altered macrophage phenotypes in ex vivo systems. These findings are exploratory, derived from a limited cohort, and support further investigation into the role of CaMKK2 in CLL biology, but do not establish independent prognostic value or direct on-target causality.

Bone and soft-tissue sarcomas are rare, heterogeneous malignancies whose surveillance remains dominated by imaging despite substantial molecular diversity and variable patterns of relapse. Circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) offer minimally invasive approaches for monitoring tumor biology, but their performance in sarcoma depends strongly on subtype, disease burden, assay design, and biological shedding.

This narrative review synthesizes evidence published from 2015 to 2026 on ctDNA and CTCs for baseline risk assessment, treatment-response monitoring, minimal residual disease (MRD) detection, molecular relapse, and integration with imaging-based surveillance in bone and soft-tissue sarcomas.

Current evidence supports a genomics-guided framework in which liquid-biopsy strategy is selected according to sarcoma subtype, molecular architecture, and clinical purpose. ctDNA is the most mature analyte, with best-supported evidence in osteosarcoma, where tumor-informed assays predict postoperative relapse, and in translocation-associated sarcomas, where breakpoint-guided assays enable highly specific longitudinal monitoring. Copy-number-based approaches are relevant for complex-karyotype tumors, while mutation-, methylation-, fragmentomic-, and RNA-based strategies may be useful in selected contexts. However, detection rates vary, false-negative results occur in low-shedding or low-volume disease, and clinical utility for changing treatment remains incompletely established. CTCs provide complementary cellular and prognostic information, particularly in osteosarcoma, but remain limited by platform heterogeneity and incomplete standardization.

Liquid biopsy may refine risk stratification, support treatment-response assessment, clarify indeterminate imaging findings, and identify molecular relapse in selected sarcoma patients. At present, it should be interpreted as an adjunct to imaging and specialist multidisciplinary care rather than as a replacement for standard radiologic surveillance.

Natural killer (NK) cells are innate lymphocytes capable of killing transformed cells without prior sensitization through direct cytolytic activity and, in an antigen-specific manner, by antibody-dependent cellular cytotoxicity (ADCC). Human NK cells mediate ADCC exclusively via the IgG Fc receptor CD16 (FcγRIIIA), triggering degranulation and cytokine production. Multi-engager complexes, such as BiKEs, TriKEs, TetraKEs, ANKETs, and ICEs, have been developed to link CD16 to tumor antigens. However, CD16 expression can be rapidly downregulated upon NK cell activation by the proteolytic checkpoint, a disintegrin and metalloproteinase-17 (ADAM17). ADAM17 induction in NK cells occurs in response to various stimuli, including the potent activating receptor CD16 and cytokine signaling. CD16 downregulation is further exacerbated within the tumor microenvironment, significantly diminishing ADCC potency by tumor-infiltrating NK cells. Moreover, ADAM17 expression and function are upregulated in various solid tumors, leading to the release of NK cell ligands and tumor-promoting factors. Consequently, developing strategies to inhibit ADAM17 to enhance NK cell function and suppress tumor cell growth is paramount to multi-engager efficacy. This review provides an overview of NK cell biology and the role of ADAM17 in regulating NK cell function and tumor cell growth. We examine the current landscape of NK cell multi-engager complexes in clinical development and discuss emerging strategies for incorporating an ADAM17-blocking component to optimize therapeutic outcomes.

Cancer remains one of the leading causes of morbidity and mortality worldwide despite remarkable advances in molecular biology, precision medicine, and targeted therapeutics [...].

The intricate intercellular communication within the tumor microenvironment (TME) critically drives cancer progression and therapeutic resistance. Natural killer (NK) cells are potent sentinels of the innate immune system, but their antitumor functions are often severely compromised by the TME's immunosuppressive networks. Moving beyond protein-coding genes, non-coding RNAs (ncRNAs)-with microRNAs (miRNAs) playing a foundational role alongside long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs)-have emerged as vital components of the regulatory networks influencing immune responses. Rather than dictating immune cell fate, these diverse transcriptomic classes form complex networks that modulate NK cell functional states and TME immunosuppression. This review systematically elucidates the molecular mechanisms by which these ncRNA networks influence NK cell biology in the TME. We dissect three core regulatory axes driven by extracellular vesicle (EV)-mediated communication, competitive endogenous RNA crosstalk, and epigenetic remodeling: the extrinsic suppression of NK cells by EV-derived and secreted ncRNAs from TME-resident cells, the reciprocal modulation of TME components by NK cell-derived ncRNAs, and the intrinsic regulation of NK cell functions by endogenous ncRNAs. Furthermore, we critically assess the clinical translational potential of targeting these networks. We highlight specific ncRNAs as non-invasive prognostic biomarkers and summarize targeted therapeutic interventions using antisense oligonucleotides, small interfering RNAs, and nano-delivery systems. Modulating these core ncRNA nodes to mitigate TME immunosuppression offers a novel paradigm for precision oncology, holding substantial promise for enhancing immune checkpoint blockade and NK cell-directed immunotherapies.

The heterogeneity of tumor cells facilitates their dynamic adaptation to tumor microenvironmental pressures throughout progression. Nevertheless, the mechanisms underlying intercellular communication and transformation among heterogeneous tumor cells remain inadequately understood. In this study, we indicate that Ephrin type-A receptor 2 (EphA2) is heterogeneously expressed in gastric cancer (GC) tumor cells, with those exhibiting elevated EphA2 (EphA2^High) expression demonstrating enhanced migratory and invasive capabilities. EphA2^High cells facilitate the transfer of EphA2 via exosomes, which subsequently localize on the membrane of EphA2^Low cells, thereby activating the ERK signaling pathway in a ligand-independent manner. This process promotes the transformation of EphA2^Low cells and contributes to the progression of GC. An investigation into the correlation between serum levels and tumor metastasis in patients with GC revealed that those with lymph node metastasis exhibited higher levels of serum exosomal EphA2. This study elucidates the process of dominant group formation within heterogeneous tumor cells and suggests the viability of exosomal EphA2 as a potential biomarker for further clinical investigation.

Nanotechnology is rapidly advancing as a promising approach in ovarian cancer management, addressing key challenges such as late diagnosis, drug resistance, and systemic toxicity of conventional therapies. Nanoparticles-engineered at the 1-100 nm scale-possess unique physical and biological properties that make them well-suited for targeted drug delivery, imaging, and biomarker detection. In diagnostics, platforms such as gold nanoparticles, quantum dots, superparamagnetic iron oxide nanoparticles (SPIONs), and carbon-based nanomaterials have demonstrated the ability to improve sensitivity and specificity, enabling the detection of low-abundance biomarkers and enhancing imaging contrast. These advances could significantly improve the early-stage detection, where survival outcomes are most favorable. Therapeutically, nanoparticles offer controlled and sustained drug release, targeted delivery to specific tumor sites, and the ability to co-deliver multiple agents, including siRNA and mRNA, in order to overcome resistance pathways. Clinically, liposomal formulations such as Doxil, already demonstrate reduced toxicity and improved drug bioavailability, while polymeric, silica, gold, and magnetic nanoparticles continue to show encouraging results in preclinical and early clinical studies. Although challenges remain-including large-scale production, long-term safety evaluation, and regulatory complexity-the current body of evidence highlights nanotechnology's transformative potential in ovarian cancer care. By enabling earlier detection, more precise targeting, and reduced systemic toxicity, nanomedicine represents a critical step toward improving both survival and quality of life in affected patients.