Nuclear factor-κB (NF-κB) transcription factors play a key role in the pathogenesis of multiple myeloma (MM). The survival, proliferation and chemoresistance of malignant plasma cells largely rely on the activation of canonical and noncanonical NF-κB pathways. They are triggered by cancer-associated mutations or by the autocrine and paracrine production of cytokines and growth factors as well as direct interaction with cellular and noncellular components of bone marrow microenvironment (BM). In this context, NF-κB also significantly affects the activity of noncancerous cells, including mesenchymal stromal cells (MSCs), which have a critical role in disease progression. Indeed, NF-κB transcription factors are involved in inflammatory signaling that alters the functional properties of these cells to support cancer evolution. Moreover, they act as regulators and/or effectors of pathways involved in the interplay between MSCs and MM cells. The aim of this review is to analyze the role of NF-κB in this hematologic cancer, focusing on NF-κB-dependent mechanisms in tumor cells, MSCs and myeloma–mesenchymal stromal cell crosstalk.

NKG2D ligands play a relevant role in Natural Killer (NK) cell -mediated immune surveillance of multiple myeloma (MM). Different levels of regulation control the expression of these molecules at cell surface. A number of oncogenic proteins and miRNAs act as negative regulators of NKG2D ligand transcription and translation, but the molecular mechanisms sustaining their basal expression in MM cells remain poorly understood. Here, we evaluated the role of the growth arrest specific 6 (GAS6)/TAM signaling pathway in the regulation of NKG2D ligand expression and MM recognition by NK cells. Our data showed that GAS6 as well as MERTK and AXL depletion in MM cells results in MICA downregulation and inhibition of NKG2D-mediated NK cell degranulation. Noteworthy, GAS6 derived from bone marrow stromal cells (BMSCs) also increases MICA expression at both protein and mRNA level in human MM cell lines and in primary malignant plasma cells. NF-kB activation is required for these regulatory mechanisms since deletion of a site responsive for this transcription factor compromises the induction of mica promoter by BMSCs. Accordingly, knockdown of GAS6 reduces the capability of BMSCs to activate NF-kB pathway as well as to enhance MICA expression in MM cells. Taken together, these results shed light on molecular mechanism underlying NKG2D ligand regulation and identify GAS6 protein as a novel autocrine and paracrine regulator of basal expression of MICA in human MM cells.

Background: Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide and is characterized by an immunosuppressive tumor microenvironment (TME). While adaptive immunity contributes to tumor control, growing evidence underscores the role of innate lymphocytes, particularly natural killer (NK) cells, in early antitumor surveillance. However, tumor-infiltrating NK cells often exhibit defective maturation and impaired effector functions, whereas the signals regulating NK cell differentiation and activity in CRC remain poorly defined. Interleukin-27 (IL-27) has emerged as a regulator of antitumor immunity, yet its role in modulating NK cell responses in intestinal tumors is largely unexplored. Methods: We employed an orthotopic transplantation model of genetically engineered colorectal tumor organoids Apc ^−/− Kras ^G12D/+ Trp53 ^R172H/− Smad4 ^−/− (AKPS) to investigate NK cell heterogeneity, maturation, and function during CRC progression. Tumor-infiltrating innate lymphocytes were analyzed using single-cell RNA sequencing, flow cytometry, immunofluorescence, and functional assays. In vitro co-culture systems and in vivo IL-27 blockade were used to assess the impact of tumor-derived IL-27 on NK cell transcriptional programs and effector activity. Results: Single-cell transcriptomic profiling revealed marked heterogeneity among tumor-infiltrating NK cells, identifying subsets with different maturation states and functional capacities. Among innate lymphocytes, AKPS tumors were dominated by NK cells displaying reduced activating receptors and diminished cytotoxic and cytokine-producing potential. Phenotypic and adoptive transfer analyses demonstrated that the TME favors persistence of immature CD27 ⁺ NK cell subsets while limiting differentiated NK cells. Mechanistically, tumor-derived IL-27 emerged as a critical regulator sustaining NK cell infiltration and activation; IL-27 blockade reduced NK cell accumulation, interferon-γ production, and immature subset frequency. The clinical relevance of these findings was supported by analysis of human CRC single-cell datasets, which revealed elevated IL-27 signaling in intratumoral NK cells, as well as by the ability of patient-derived organoids to enhance NK-cell cytotoxicity, which was reduced by IL-27 blockade. Conclusions: Our study identifies IL-27 as a critical modulator of NK cell differentiation and function in CRC, highlighting its role in sustaining NK cell-mediated immune surveillance within the tumor microenvironment. These findings provide mechanistic insight into NK cell dysfunction in CRC and suggest IL-27 signaling as a promising therapeutic target to restore innate antitumor immunity.