The Grim RIPper: Cells can undergo regulated cell death through distinct processes known as apoptosis and necrosis. Regulation of apoptosis is better understood than that of necrosis. In a screen for gene products that participate in control of necrosis in cells treated with TNF (tumor necrosis factor), D.-W. Zhang et al. (p. 332 ; published online 4 June) identified a protein kinase, RIP3. In cells treated with TNF and a caspase inhibitor that inhibits apoptosis, seven metabolic enzymes interacted with RIP3, some of which are associated with mitochondria. Generation of reactive oxygen species was necessary for TNF-induced necrosis, and depletion of RIP3 reduced the generation of reactive oxygen species. Thus, RIP3 may participate in the mechanisms that link energy metabolism with mechanisms of cell death.

Glioblastoma (GBM), the predominant and primary malignant intracranial tumor, poses a formidable challenge due to its immunosuppressive microenvironment, thereby confounding conventional therapeutic interventions. Despite the established treatment regimen comprising surgical intervention, radiotherapy, temozolomide administration, and the exploration of emerging modalities such as immunotherapy and integration of medicine and engineering technology therapy, the efficacy of these approaches remains constrained, resulting in suboptimal prognostic outcomes. In recent years, intensive scrutiny of the inhibitory and immunosuppressive milieu within GBM has underscored the significance of cellular constituents of the GBM microenvironment and their interactions with malignant cells and neurons. Novel immune and targeted therapy strategies have emerged, offering promising avenues for advancing GBM treatment. One pivotal mechanism orchestrating immunosuppression in GBM involves the aggregation of myeloid-derived suppressor cells (MDSCs), glioma-associated macrophage/microglia (GAM), and regulatory T cells (Tregs). Among these, MDSCs, though constituting a minority (4–8%) of CD45⁺ cells in GBM, play a central component in fostering immune evasion and propelling tumor progression, angiogenesis, invasion, and metastasis. MDSCs deploy intricate immunosuppressive mechanisms that adapt to the dynamic tumor microenvironment (TME). Understanding the interplay between GBM and MDSCs provides a compelling basis for therapeutic interventions. This review seeks to elucidate the immune regulatory mechanisms inherent in the GBM microenvironment, explore existing therapeutic targets, and consolidate recent insights into MDSC induction and their contribution to GBM immunosuppression. Additionally, the review comprehensively surveys ongoing clinical trials and potential treatment strategies, envisioning a future where targeting MDSCs could reshape the immune landscape of GBM. Through the synergistic integration of immunotherapy with other therapeutic modalities, this approach can establish a multidisciplinary, multi-target paradigm, ultimately improving the prognosis and quality of life in patients with GBM.

Necrotic death of macrophages has long been known to be present in atherosclerotic lesions but has not been studied. We examined the role of receptor interacting protein (RIP) 3, a mediator of necrotic cell death, in atherosclerosis and found that RIP3(-/-);Ldlr(-/-) mice were no different from RIP3(+/+);Ldlr(-/-) mice in early atherosclerosis but had significant reduction in advanced atherosclerotic lesions. Similar results were observed in Apoe(-/-) background mice. Bone marrow transplantation revealed that loss of RIP3 expression from bone-marrow-derived cells is responsible for the reduced disease progression. While no difference was found in apoptosis between RIP3(-/-);Ldlr(-/-) and RIP3(+/+);Ldlr(-/-) mice, electron microscopy revealed a significant reduction of macrophage primary necrosis in the advanced lesions of RIP3(-/-) mice. In vitro cellular studies showed that RIP3 deletion had no effect on oxidized low-density lipoprotein (LDL)-induced macrophage apoptosis, but prevented macrophage primary necrosis occurring in response to oxidized LDL under caspase inhibition or RIP3 overexpression conditions. RIP3-dependent necrosis is not postapoptotic, and the increased primary necrosis in advanced atherosclerotic lesions most likely resulted from the increase of RIP3 expression. Our data demonstrate that primary necrosis of macrophages is proatherogenic during advanced atherosclerosis development.

Receptor-interacting protein (RIP) kinases are a group of threonine/serine protein kinases with a relatively conserved kinase domain but distinct non-kinase regions. A number of different domain structures, such as death and caspase activation and recruitment domain (CARD) domains, were found in different RIP family members, and these domains should be keys in determining the specific function of each RIP kinase. It is known that RIP kinases participate in different biological processes, including those in innate immunity, but their downstream substrates are largely unknown. This review will give an overview of the structures and functions of RIP family members, and an update of recent progress in RIP kinase research.

Precursor messenger RNA (pre-mRNA) splicing is catalyzed by an intricate ribonucleoprotein complex called the spliceosome. Although the spliceosome is considered to be general cell “housekeeping” machinery, mutations in core components of the spliceosome frequently correlate with cell- or tissue-specific phenotypes and diseases. In this review, we expound the links between spliceosome mutations, aberrant splicing, and human cancers. Remarkably, spliceosome-targeted therapies (STTs) have become efficient anti-cancer strategies for cancer patients with splicing defects. We also highlight the links between spliceosome and immune signaling. Recent studies have shown that some spliceosome gene mutations can result in immune dysregulation and notable phenotypes due to mis-splicing of immune-related genes. Furthermore, several core spliceosome components harbor splicing-independent immune functions within the cell, expanding the functional repertoire of these diverse proteins.