NF-κB-inducing kinase (NIK; also known as MAP3K14) is a central regulator of non-canonical NF-κB signaling in response to stimulation of TNF receptor superfamily members, such as the lymphotoxin-β receptor (LTβR), and is implicated in pathological angiogenesis associated with chronic inflammation and cancer. Here, we identify a previously unrecognized role of the LTβR–NIK axis during inflammatory activation of human endothelial cells (ECs). Engagement of LTβR-triggered canonical and non-canonical NF-κB signaling promoted expression of inflammatory mediators and adhesion molecules, and increased immune cell adhesion to ECs. Sustained LTβR-induced inflammatory activation of ECs was NIK dependent, but independent of p100, indicating that the non-canonical arm of NF-κB is not involved. Instead, prolonged activation of canonical NF-κB signaling, through the interaction of NIK with IκB kinase α and β (also known as CHUK and IKBKB, respectively), was required for the inflammatory response. Endothelial inflammatory activation induced by synovial fluid from rheumatoid arthritis patients was significantly reduced by NIK knockdown, suggesting that NIK-mediated alternative activation of canonical NF-κB signaling is a key driver of pathological inflammatory activation of ECs. Targeting NIK could thus provide a novel approach for treating chronic inflammatory diseases.

Treatment of solid tumors remains challenging and therapeutic strategies require continuous development. Tumor-infiltrating macrophages play a pivotal role in tumor dynamics. Here, we present a Macrophage-Drug Conjugate (MDC) platform technology that enables loading macrophages with ferritin-drug complexes. We first show that macrophages actively take up human heavy chain ferritin (HFt) in vitro via macrophage scavenger receptor 1 (MSR1). We further manifest that drug-loaded macrophages transfer ferritin to adjacent cancer cells through a process termed ‘TRAnsfer of Iron-binding protein’ (TRAIN). The TRAIN process requires direct cell-to-cell contact and an immune synapse-like structure. At last, MDCs with various anti-cancer drugs are formulated with their safety and anti-tumor efficacy validated in multiple syngeneic mice and orthotopic human tumor models via different routes of administration. Importantly, MDCs can be prepared in advance and used as thawed products, supporting their clinical applicability. This MDC approach thus represents a promising advancement in the therapeutic landscape for solid tumors.

Triple-negative breast cancer (TNBC) is a challenging subtype of breast cancer characterized by the absence of estrogen and progesterone receptors and HER2 expression, leading to limited treatment options and a poorer prognosis. TNBC is particularly prevalent in premenopausal African-descent women and is associated with aggressive tumor behavior and higher metastatic potential. Tumor-associated macrophages (TAMs) are abundantly present within the TNBC microenvironment and play pivotal roles in promoting tumor growth, progression, and metastasis through various mechanisms, including immune suppression and enhancement of angiogenesis. This review provides an in-depth overview of TNBC, focusing on its epidemiology, its molecular characteristics, and the critical influence of TAMs. It discusses the pathological and molecular aspects that define TNBC’s aggressive nature and reviews current and emerging therapeutic strategies aimed at targeting these dynamics. Special attention is given to the role of TAMs, exploring their potential as therapeutic targets due to their significant impact on tumor behavior and patient outcomes. This review aims to highlight the complexities of the TNBC landscape and to present the innovative approaches that are currently being pursued to improve therapeutic efficacy and patient survival.

In 2024, the United States was projected to experience 2 million new cancer diagnoses and approximately 611,720 cancer-related deaths, reflecting a broader global trend in which cancer cases are anticipated to exceed 35 million by 2050. This increasing burden highlights ongoing challenges in cancer treatment despite significant advances that have reduced cancer mortality by 31% since 1991. Key obstacles include the disease’s inherent heterogeneity and complexity, such as treatment resistance, cancer stem cells, and the multifaceted tumor microenvironment (TME). The TME—comprising various tumor and immune cells, blood vessels, and biochemical factors—plays a crucial role in tumor growth and resistance to therapies. Recent innovations in cancer treatment, particularly in the field of immuno-oncology, have leveraged insights into TME interactions. An emerging example is the FDA-approved therapy using tumor-infiltrating lymphocytes (TILs), demonstrating the potential of cell-based approaches in solid tumors. However, TIL therapy is just one of many strategies being explored. This review provides a comprehensive overview of the emerging field of immuno-oncology, focusing on how novel therapies targeting or harnessing components of the TME could enhance treatment efficacy and address persistent challenges in cancer care.

Ovarian cancer is a leading cause of cancer-related deaths among women, with platinum resistance posing a significant challenge. Conventional therapies often fail in these cases, highlighting the urgent need for novel treatment approaches. Immunotherapy has emerged as a promising strategy, offering renewed hope for patients with platinum-resistant ovarian cancer (PROC). This review explores the current landscape of immunotherapies for PROC, discussing different approaches, their mechanisms of action, and the potential for overcoming the limitations of conventional treatments.

The application of nanotechnology in medicine has garnered significant interest, particularly in the development of advanced drug delivery systems. Graphene oxide (GO) shows promise as a carrier for delivering microRNA (miRNA) mimics or antisense constructs. miRNAs play a crucial role in regulating gene expression, and their dysregulation is associated with various diseases, including cancer. This study aimed to evaluate the impact of graphene oxide on cellular signaling pathways and its potential as a platform for gene delivery by developing a GO–antisense miRNA-21 nanosystem in HepG2 liver cancer cells. A colloidal dispersion of GO was used to prepare GO-antisense miRNA-21 nanosystems via self-assembly. The nanosystem was characterized in terms of ultrastructure, size distribution, surface composition and binding by TEM, DLS, ATR-FTIR and UV-Vis spectra. Zeta potential measurements were conducted to evaluate nanosystem stability by assessing the release kinetics of antisense miRNA-21. The efficiency of the GO nanosystem in delivering antisense miRNA-21 into HepG2 cells was analyzed using confocal microscopy and flow cytometry. Given the central role of miRNA-21 in inflammatory and oncogenic pathways, we first assessed its expression following GO exposure. In line with previous studies reporting high miRNA-21 expression in hepatocellular carcinoma cells, GO treatment further increased miRNA-21 levels in HepG2 cells compared with untreated controls. Changes in the expression levels of IL-8, MCP-1, ICAM-1, TIMP-2, and NF-kB were quantified by qPCR analysis. The ultrastructural analysis confirmed a strong affinity between GO and antisense miRNA-21. Transfection results demonstrate that the GO-based nanosystem effectively delivered antisense miRNA-21 into HepG2 cells, leading to a reduction in the expression of key pro-inflammatory genes. These findings suggest that GO-based nanocarriers may offer a promising strategy for delivering localized intratumoral miRNA-based therapies that target gene regulation in hepatocellular carcinoma.