Pancreatic ductal adenocarcinoma (PDAC) presents significant oncological challenges due to its aggressive nature and poor prognosis. The tumor microenvironment (TME) plays a critical role in progression and treatment resistance. Non-neoplastic cells, such as cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs), contribute to tumor growth, angiogenesis, and immune evasion. Although immune cells infiltrate TME, tumor cells evade immune responses by secreting chemokines and expressing immune checkpoint inhibitors (ICIs). Vascular components, like endothelial cells and pericytes, stimulate angiogenesis to support tumor growth, while adipocytes secrete factors that promote cell growth, invasion, and treatment resistance. Additionally, perineural invasion, a characteristic feature of PDAC, contributes to local recurrence and poor prognosis. Moreover, key signaling pathways including Kirsten rat sarcoma viral oncogene (KRAS), transforming growth factor beta (TGF-β), Notch, hypoxia-inducible factor (HIF), and Wnt/β-catenin drive tumor progression and resistance. Targeting the TME is crucial for developing effective therapies, including strategies like inhibiting CAFs, modulating immune response, disrupting angiogenesis, and blocking neural cell interactions. A recent multi-omic approach has identified signature genes associated with anoikis resistance, which could serve as prognostic biomarkers and targets for personalized therapy.

ADAM17 (a disintegrin and metalloproteinase 17) is increasingly recognized as a central regulator of multiple myeloma (MM) biology beyond its canonical role in TNF-α shedding. Rather than acting as a classical oncogenic driver, ADAM17 functions as a master regulator of ectodomain shedding, controlling the balance between membrane-bound and soluble mediators that shape signaling across the bone marrow microenvironment. Through coordinated processing of cytokines, cytokine receptors, growth factor ligands, and adhesion molecules, ADAM17 amplifies inflammatory signaling, endothelial activation, immune dysfunction, and tumor dissemination.In MM, ADAM17 contributes to key pathogenic processes by modulating the spatial and temporal dynamics of extracellular communication. Shedding of CX3CL1 and adhesion molecules such as JAM-A promotes angiogenesis and vascular niche remodeling, while IL-6R cleavage enables trans-signaling that sustains stromal activation, chronic inflammation, and malignant plasma cell survival. In parallel, ADAM17-dependent processing of immune receptors, including CD62L, alters lymphocyte trafficking and immune surveillance, contributing to an immunologically permissive niche. Proteolytic remodeling of adhesion systems may also facilitate niche escape and extramedullary dissemination.These coordinated shedding events define a dynamic myeloma “sheddome,” in which ADAM17 acts as a systems-level node integrating tumor, stromal, endothelial, and immune signals. This framework helps explain the context-dependent and pleiotropic effects of ADAM17 throughout disease evolution. Clinically, circulating ADAM17 shows promise as a dynamic biomarker reflecting tumor burden, microenvironmental activation, and immune dysfunction. However, therapeutic targeting remains challenging because of substrate redundancy, systemic functions, and the risk of disrupting physiological immune regulation. Future strategies will require selective and context-aware modulation of ADAM17-driven shedding networks to effectively reprogram the myeloma microenvironment.