Endocytosis mediates the internalization of extracellular cargo via vesicular trafficking, enabling targeted delivery to specific organelles and maintaining cellular homeostasis. Endosomes function as dynamic hubs that orchestrate intracellular communication. While they primarily internalize material from the cell surface, their role extends far beyond passive transport. Through continuous cycles of sorting, fusion, and fission, endosomes engage in extensive crosstalk with other organelles via three fundamental modes: vesicle-mediated cargo transport, membrane contact site-mediated non-vesicular exchange, and signaling and mechanical coupling. These interorganellar interactions enable the transfer of metabolites, lipids, and signals, positioning endosomes as central regulators of cellular homeostasis. While interest in these contacts is growing, a systematic understanding of their roles is still needed. This review explores the protein machinery involved, examines how endosome-organelle contacts coordinate transport and remodeling, and discusses their impact on homeostasis and disease when dysregulated. We underscore the importance of the endosomal communication network in adaptive responses and provide perspectives for targeting endosome-related pathologies.

Poly(ADP-ribose) polymerase 1 (PARP1) inhibition represents a promising targeted therapy for BRCA-deficient cancer patients based on the synthetic lethality theory. Recent evidence shows that the efficacy of DNA damage drugs depends on two aspects: DNA repair signaling and immune response. Applying a functional proteomics approach, we find that the function of the spliceosome is perturbed by PARP inhibitors via enhancing interaction between PARP1 and SF3B1, a key factor of the spliceosome. We demonstrate that differential alternative spliced mRNA and accumulation of double-stranded RNA (dsRNA) are induced by perturbation of the spliceosome upon PARP inhibitor treatment, resulting in triggering dsRNA antiviral mimicry innate immune response. Moreover, we identify a novel function of BRCA1, through which BRCA1 regulates innate immune response, leading to compromising of the innate immune signaling by downregulation of IRF3 in BRCA1-deficient breast cancer cells, which reduces the sensitivity to PARP inhibitors and causes intrinsic resistance. Polyinosinic–polycytidylic acid (poly(I:C)) is a dsRNA synthetic analog sensitizing PARP inhibitors through further triggering dsRNA signaling. Finally, we show that the combination of PARP inhibitors and poly(I:C) enhances anti-tumor efficiency in vivo. Overall, our study reveals that BRCA1 deficiency impedes tumor cell intrinsic innate immune response, inducing intrinsic resistance to PARP inhibitors that can be overcome when poly(I:C) is combined.

¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) is the most widely used radiotracer for positron emission tomography (PET) imaging in clinical oncology, owing to the elevated glycolytic activity of tumor cells. However, transient post-radiotherapy (RT) “metabolic flares” of ¹⁸F-FDG uptake are frequently observed in patients and are traditionally attributed to localized inflammatory responses. Whether these flares are linked to immune cell dynamics, particularly tumor-infiltrating T cells, and the mechanisms involved remain poorly understood. Here, we demonstrate that RT markedly upregulates intracellular adhesion molecule-1 (ICAM-1) expression and promotes T cell infiltration in tumors, as observed in both patients and mouse models. Genetic ablation of ICAM-1 significantly attenuates RT-induced metabolic flares in irradiated tumors, primarily due to reduced ¹⁸F-FDG uptake by tumor-infiltrating T cells rather than myeloid cells. Mechanistically, ICAM-1 engages with lymphocyte function-associated antigen 1 (LFA-1) to facilitate T cell clustering, thereby promoting their intratumoral accumulation and activating glycolysis and the tricarboxylic acid cycle via the PI3K-AKT-mTOR signaling pathway. These findings identify ICAM-1 as a critical regulator of T cell metabolic reprogramming and tumor infiltration following RT, offering a mechanistic explanation for ¹⁸F-FDG PET flares. Clinical monitoring of post-RT tumor ICAM-1 expression may enhance PET interpretation and aid in distinguishing pseudoprogression from true tumor progression.

Nipah virus (NiV) poses a significant public health threat due to its high mortality rate and the absence of approved treatments. Nonetheless, the host–virus interactions underlying its pathogenesis remain poorly understood. Here, we identified the 5-methylcytosine (m⁵C) methyltransferase NSUN2 as a critical host factor hijacked by NiV to facilitate replication via dual mechanisms. The viral matrix (M) protein stabilizes NSUN2 by inhibiting its proteasomal degradation. In turn, NSUN2 catalyzes m⁵C deposition on NiV RNAs, enhancing M RNA stability and protein expression. Simultaneously, NSUN2’s noncatalytic domain engages GNB2 as an adaptor to facilitate the recruitment of the E3 ubiquitin ligase TRIM28 to M, promoting M ubiquitination and consequent nuclear export for virion assembly. Targeting both pathways using the proteasome inhibitor carfilzomib and the m⁵C inhibitor MY-1B suppressed NiV replication in vitro and in hamsters. Our findings uncover a dual epigenetic–posttranslational regulatory axis exploited by NiV and present a promising combinatorial therapeutic approach.