Aug 2026· PLoS Pathogens· Vol 22 8, pp.
e1014498
· 0 citations· 64 references
Medicine
TL;DR
The results suggest that intracellular T. annulata and T. parva parasites could drive an immune evasion cancer hallmark in host lymphocytes by epigenetic silencing of genes for innate and adaptive immunity.
Abstract
Cancer hallmarks are characterized by wide-scale changes in gene expression programs. Pioneering studies showed how viral oncogenes target regulatory pathways, but little is known about tumorigenic mechanisms of non-viral pathogens. Theileria annulata is an intracellular parasite (related to apicomplexa parasites causing malaria) which remarkably transforms bovine leukocytes, hijacking host signaling pathways to induce cancer phenotypes, akin to human leukemias. While some host genes contribute to the proliferative or invasive hallmark phenotypes, there is still limited comprehensive understanding of the impact of Theileria infection on host transcription and transformation. We performed a multi-omics meta-analysis to investigate the effect of Theileria infection on cancer hallmarks in bovine B lymphocytes. Combining transcriptomic, proteomic and epigenomic analysis across multiple datasets, we show that Theileria infection suppresses host immune pathways. Specifically, genes encoding innate and adaptive immune mediators are repressed in T. annulata-infected B cells (and in T. parva infected T cells), including downregulation of genes for Toll-like receptors (TLR), inflammasome components of the guanylate binding protein (GBP) family and major histocompatibility complex class (MHC) II genes. Treatment with distinct theilericidal drugs could partially rescue immune gene expression. Mechanistically, we describe alterations in the host epigenome, including loss of activating histone modifications (e.g., H3K18ac, H3K4me3, H3K27ac) on the promoters of repressed immune genes, and enrichment of silencing marks (H3K27me3) on promoters of the BOLA genes and the gene encoding CIITA, the master transcriptional regulator of MHC class II gene expression. Our results suggest that intracellular T. annulata and T. parva parasites could drive an immune evasion cancer hallmark in host lymphocytes by epigenetic silencing of genes for innate and adaptive immunity.
This study proposes that PGCCs represent an immune-adaptive polyploid survival state in which inflammatory and ontogenetic pathways are repurposed to support immune evasion and tumor persistence and provides a framework for therapeutic strategies aimed at dismantling the PGCC reservoir and preventing tumor relapse.
O. Anatskaya, Alexander E. Vinogradov· International Journal of Mol...· 0 citations
Genome-wide CRISPR screens have systematically identified genes required for cancer cell survival, yet these studies are typically performed under standardized conditions that do not fully recapitulate the physiological stresses encountered within the tumor microenvironment. In a recent issue of Nature Genetics, Cheruiyot and colleagues perform genome-wide loss-of-function screens under inflammatory conditions induced by interferon-β (IFN-β), interferon-γ (IFN-γ), and tumor necrosis factor (TNF), revealing that distinct cytokines impose different genetic requirements for tumor cell survival. The study shows that inflammatory signaling reshapes genetic dependency landscape in a cytokine-specific manner. Mechanistic analyses identify the glycosylphosphatidylinositol (GPI) transamidase complex and FITM2 as representative examples of genes that become selectively required under inflammatory stress by maintaining membrane protein maturation, endoplasmic reticulum homeostasis, and resistance to oxidative stress. These findings broaden our understanding of how inflammatory cytokines influence tumor cell biology beyond transcriptional regulation and immune recognition. More broadly, the study highlights the value of incorporating physiologically relevant conditions into functional genetic screens, suggesting that conventional dependency maps capture only part of the genetic requirements for tumor survival. Applying similar approaches to other microenvironmental stresses-including hypoxia, metabolic competition, extracellular matrix remodeling, and stromal signaling-may uncover additional therapeutic opportunities for cancer immunotherapy.
Zihan Ning, Guangchuan Wang· Cancer Research· 0 citations
Immune checkpoint inhibitors (ICIs) have revolutionized lymphoma treatment, yet resistance driven by complex regulatory networks remains a major hurdle. Circular RNAs (circRNAs) have emerged as central signaling hubs that integrate metabolic, inflammatory, and oncogenic cues to fine-tune immune checkpoints such as PD-L1 and CD47 in lymphoma. Here, we systematically dissect the molecular mechanisms by which circRNAs govern immune checkpoints in lymphoma, including nuclear transcriptional control, interactions with RNA-binding proteins (RBPs), competitive endogenous RNA (ceRNA) networks, and micropeptide translation. We differentiate between cell-extrinsic, exosome-mediated reprogramming of the tumor microenvironment and cell-intrinsic circRNA circuits within lymphoma cells spatially. Subtype-specific investigations demonstrate the importance of Epstein-Barr virus (EBV)-encoded circRNAs in immune evasion and the synergistic interactions between 9p24.1 amplification and circRNAs in classical Hodgkin lymphoma (cHL). While therapeutic approaches including antisense oligonucleotides, CRISPR-Cas13, and nanodelivery technologies demonstrate preclinical synergy with ICIs, circulating circRNAs show potential as dynamic indicators for predicting ICI responses. We also critically examine ongoing discussions about the flaws of current model systems, the technological constraints of current validation techniques, and the physiological significance of the ceRNA hypothesis. Positioning circRNAs as multimodal regulatory hubs, this review provides a theoretical framework for developing circRNA-based immunotherapies to overcome resistance in lymphoma.
Jingjing Liu, Tianhua Zhao, Yanning Wu et al.· Frontiers in Immunology· 0 citations
Acquired resistance in cancer is a major obstacle to durable response after immune checkpoint blockade (ICB). While interferon (IFN) signaling is frequently linked with effective ICB response, prolonged interferon signaling within cancer cells paradoxically drives immune suppression. In preclinical mouse models of ICB, relapsed tumors possess an altered epigenetic landscape characterized by inflammatory memory domain accessibility maintained by STAT1 and IRF3. Here, we restore ICB response by identifying and targeting pathways that maintain IFN-associated memory and resistance.
Res 499 tumor cells derived from a late-relapse B16 melanoma were manipulated as indicated, flank-injected into C57BL/6 mice, and treated with ICB. Tumors were harvested on day 16 post-implantation for RNA-seq, ATAC-seq, and flow cytometry.
Prolonged exposure of cancer cells to IFN selectively increases the expression of a subset of IFNy stimulated genes, or “memory ISGs”, which are enriched for immune evasive properties. Moreover, persistent IFN signaling induces elevated expression of not only dsRNA-forming endogenous retroelements (EREs), but also of IFN-inducing dsRNA sensors such as MDA5, establishing a STAT1 and IRF3 activating feed-forward loop. Consequently, knock out of MDA5, or pharmacological blockade of IFN and MDA5 signaling via JAK1/2 and TBK1 inhibitors respectively, lowers ERE expression, decreases chromatin accessibility at inflammatory memory loci, and increases ICB sensitivity. Via flow cytometry, we observe that ex vivo JAKi and TBK1i treatment, in a cancer cell intrinsic manner, induces a more stem-like CD8 T cell response following ICB, possibly through improved interactions with myeloid cells. Given emerging clinical data supporting JAK inhibition in ICB-refractory tumors, these findings may suggest additional benefits from targeting TBK1 as well.
Combined JAK and TBK1 inhibition attenuates inflammatory memory associated resistance and enhances ICB efficacy.
Mark Foundation for Cancer Research
Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)
Nathan Dangle, Jingya Qiu, D. Ye et al.· Journal of Immunology· 0 citations
Immune checkpoint blockade (ICB) has reshaped the treatment landscape for many malignancies, yet only a subset of patients achieve durable clinical benefit. Both primary and acquired resistance remain major barriers to long-term disease control. As central innate immune cells in the tumor microenvironment, tumor-associated macrophages (TAMs) have emerged as key contributors to this resistance. Beyond their well-recognized role in suppressing T-cell responses, TAMs influence stromal organization, metabolic stress, checkpoint ligand expression, and phagocytic activity within the TME. They also affect the intratumoral distribution and clearance of therapeutic antibodies. In this review, we discuss TAM-mediated resistance to ICB as a molecularly regulated innate immune process that is dynamic and adaptive. We consider how macrophages are recruited to tumors, how they are educated by local microenvironmental cues, and how innate immune signaling, metabolic regulation, and phagocytic checkpoints shape suppressive programs that limit the efficacy of ICB. This framework allows us to distinguish macrophage programs that recur across tumor types from those shaped by specific tissue contexts or tumor lineages, and to place diverse TAM subsets within a clinically relevant model of ICB resistance. We also review current TAM-directed therapeutic strategies, including CSF1/CSF1R blockade, inhibition of chemokine-dependent recruitment, metabolic and epigenetic reprogramming, targeting of phagocytosis checkpoints, and emerging delivery-based approaches. Although these strategies are supported by substantial mechanistic evidence, their clinical activity has so far been variable. This inconsistency likely reflects the marked heterogeneity and plasticity of TAMs, compensatory signaling pathways, spatial constraints within tumors, treatment-induced adaptation, toxicity, and the lack of robust biomarkers for patient selection. We propose that future TAM-directed therapies should move beyond broad macrophage depletion or nonspecific suppression. Instead, more precise approaches are needed—ones that are matched to dominant macrophage programs, informed by spatial and functional profiling, and guided by predictive biomarkers. Such strategies may help preserve beneficial innate immune macrophage functions while selectively disrupting the TAM states that sustain resistance to ICB.
Yu-Zhe Huang, Jun-Qi Zhang, Kaipeng Tu et al.· Frontiers in Immunology· 0 citations
The microbiome shapes host immunity, yet the molecular signals by which specific bacteria modulate innate defenses remain poorly understood. In Caenorhabditis elegans, the Intracellular Pathogen Response (IPR) is a transcriptional program activated by obligate intracellular pathogens and shares features with mammalian type I interferon responses. We aimed to identify microbiome-derived triggers of the IPR and mechanisms of host protection.
We screened twelve native bacterial isolates using an IPR GFP reporter. Reporter activation in different tissues was observed by microscopy, and bacterial inactivation or RNA treatments were used to identify the molecular triggers. Transcriptomic profiling (RNA-seq, qRT-PCR) identified host genes induced by bacterial exposure. Pathogen burden was quantified by FISH, and developmental assays measured fitness effects.
Stenotrophomonas indicatrix (JUb19) robustly activated the IPR in intestine, epidermis, neurons, and somatic gonad despite residing extracellularly, making it the first non-invasive bacterium known to trigger this pathway. Heat-killed bacteria failed to induce the IPR, whereas chemical or mechanical inactivation retained activity, implicating a heat-labile trigger. Bacterial RNA contributed to IPR activation, revealing microbiome RNA as a novel immune signal. Transcriptomic analyses showed induction of IPR genes, lysozymes, and metabolic regulators that enhance resistance to intracellular pathogens, with modest fitness costs. Remarkably, protection was inherited by naïve progeny that had never been exposed to JUb19.
Our findings identify a previously unrecognized extracellular mechanism by which microbiome-derived RNA activates epithelial immunity and provides intergenerational protection in C. elegans, linking commensal bacteria, RNA signaling, and heritable host defense.
n/a
Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)
V. Lažetić, Jordan D. West, Samuel K. Schwartz· Journal of Immunology· 0 citations
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