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.

Triple-negative breast cancer (TNBC) is characterized by a lack of estrogen, progesterone, and HER2 receptors; an aggressive phenotype; high rates of early relapse and metastasis; and the worst mortality rates among all breast cancer subtypes. Currently, there is no effective curative targeted therapy for TNBC and chemotherapy remains the primary treatment for TNBC. Therefore, there is a critical need to develop highly effective, novel therapies to improve patient survival. We previously validated FOXM1, a proto-oncogenic transcription factor, for the first time as a potential molecular target in TNBC through genetic knockdown studies in mice. We show that FOXM1 expression is associated with shorter patient survival and is a marker of poor prognosis. There is no FDA-approved FOXM1 inhibitor. We found that patients with TP53 mutations have dramatically higher FOXM1 expression, indicating that widespread TP53 mutations detected in about 80% of TNBC patients are the major driver of FOXM1 overexpression in TNBC patients. We identified its binding ability using an in silico study, and found it to be a well-known FOXM1 inhibitor that suppresses TNBC cell proliferation, migration, and invasion, and induces apoptosis. In vivo studies in mice bearing TNBC tumors demonstrated that treatment with a novel FOXM1 inhibitor incorporated in single-lipid nanoparticles suppressed the growth of TNBC tumor xenografts. In conclusion, our findings suggest that the novel FOXM1 inhibitor represents a potent and safe therapeutic strategy with significant potential for the treatment of other FOXM1-driven cancers including TNBC that currently have limited treatment options.

Perineural invasion (PNI) is a distinct route of cancer spread associated with neuropathic pain, local recurrence, and poor survival across many solid tumours. Increasing evidence shows that PNI is not only a structural pattern of invasion but also a dynamic biological process involving neurodegeneration, nociceptor sensitisation, and marked local immunosuppression. This narrative review synthesises experimental, translational, and clinical data on the molecular, neurological, and immunological mechanisms of PNI in solid malignancies. PNI arises through complex crosstalk between tumour cells, Schwann cells, macrophages, fibroblasts, and neurotrophic pathways, leading to peripheral nerve remodelling, axonal degeneration, and abnormal regeneration. These changes promote neuropathic pain through ion-channel dysregulation, neurotrophin-driven sensitisation, and pathological neuroplasticity. At the same time, PNI creates an immunosuppressive microenvironment enriched in Tregs, M2 macrophages, and myeloid-derived suppressor cells, shaped by cholinergic, adrenergic, and neuropeptidergic signalling, which may contribute to immune exclusion and resistance to immunotherapy. We propose that PNI should be understood as a neuro-immuno-metabolic process and that recognising the PNI-pain-immunosuppression triad may support the development of targeted neuroprotective, analgesic, and immunomodulatory therapies.

These are the third Canadian consensus guidelines on the management of acute myeloid leukemia (AML) in older patients. The first was published in 2013, and the second in 2017. The management of AML in older patients changed significantly over this time span, with decreasing emphasis on the use of intensive chemotherapy and the adoption of new standards of care based on less-intensive therapies: first azacitidine + venetoclax combinations, followed by azacitidine + ivosidenib. Increased use of these new therapies in older patients has raised questions about their use, including how to determine patient suitability, select the most effective therapy, and manage dosing and toxicity. In this third Canadian guideline, we address these questions to provide clarity around these new standards of care and improve clinician understanding and confidence in using them. As more new targeted agents become available and hypomethylating agent-based triplet combinations are used more widely, we fully anticipate that we will, in some years' time, write a fourth guideline on the management of AML in older patients.

First-line (1L) therapy for mantle cell lymphoma (MCL) continues to evolve rapidly, with several recent phase II and phase III trials consistently showing the activity of novel covalent Bruton's tyrosine kinase inhibitor (cBTKi) combinations. Historical treatment selection criteria such as patient age, fitness, and eligibility for autologous stem cell transplantation generally remain applicable for some, but not all, of these novel regimens. This potential for flexibility necessitates the consideration of additional factors during decision-making, such as MCL biology, patient risk tolerance, logistical and resource implications, and the impact on use of later-line options. This paper presents three illustrative patient cases to explore 1L therapy selection among these new and emerging cBTKi options. The realized and anticipated benefits, limitations, and challenges and persisting evidence gaps associated with these regimens are discussed.