Deyu Fang

The T-cell-mediated antitumor immune response has emerged as a key axis for controlling cancer growth and progression, as shown by the widespread success of immune checkpoint blockade (ICB). Unfortunately, ICB therapy still fails in a large percentage of patients, and there is a growing need to identify novel targets to increase anticancer immunity and enhance existing treatments. Among emerging therapeutic targets, deubiquitinases (DUBs) have attracted increasing attention because of their central role in regulating ubiquitin signaling. As key components of the ubiquitin system, DUBs catalyze the removal of ubiquitin from substrate proteins, thereby dynamically reversing ubiquitination and fine-tuning protein stability, localization, activity, and protein‒protein interactions. Accumulating evidence indicates that DUBs regulate not only tumor-intrinsic pathways that promote immune evasion but also T-cell activation, differentiation, and effector function, positioning them as promising therapeutic targets at the interface between cancer and immunity. However, DUBs are rarely considered holistically involved in both T-cell immunity and tumor-intrinsic immune evasion, despite the growing appreciation that individual DUBs often act in both compartments. In this review, we comprehensively examine the roles of DUBs in T-cell immunity and tumor-intrinsic immune evasion and discuss perspectives on therapeutic strategies targeting DUBs along this axis.

NK cell-based therapies for solid tumors are limited by poor persistence and progressive functional impairment. Here, we investigated how the strength of NKG2D stimulation shapes NK cell fate and therapeutic efficacy. Using B10G5, a MICA/B-targeting partial agonist antibody that attenuates NKG2D stimulation, we show that reduced NKG2D stimulation reshapes the intratumoral NK cell compartment by enriching EOMES ^hi TCF1 ^hi stem-like NK (stemNK) cell pool, preserving functional diversity, and limiting mitochondrial oxidative stress and exhaustion induced by chronic sMIC/MIC exposure. Mechanistically, we identified the H3K27me3 demethylase KDM6B as a conserved regulator of NK cell stemness whose enzymatic activity is required to maintain the intratumoral stemNK cell pool. Conversely, strong NKG2D stimulation induced mitochondrial ROS accumulation and upregulated the inhibitory receptor LAG3 on NK cells. Attenuated NKG2D stimulation on human NK cells increased KDM6B expression and reduced repressive H3K27me3 mark at the TCF7 locus. Importantly, attenuated NKG2D stimulation during ex vivo expansion enhanced human NK cell in vivo persistence and antitumor efficacy following adoptive transfer. Together, these findings establish NKG2D stimulation strength as a key determinant of NK cell fate and function in solid tumors and identify a translatable concept to improve NK cell-based immunotherapy for solid tumors.

Metastatic castration-resistant prostate cancer (mCRPC) remains a leading cause of cancer-related mortality in men. Although poly(ADP-ribose) polymerase (PARP) inhibitors are approved for mCRPC patients with homologous recombination repair (HRR) deficiencies, clinical trials combining olaparib with PD-1/PD-L1 inhibitors showed limited efficacy in unselected populations. To investigate the immunomodulatory effects of PARP inhibitors in an unbiased manner, we performed bulk RNA-seq on HRR-proficient MycCaP cells treated with the PARP inhibitor olaparib versus vehicle control. Transcriptomic analysis revealed robust upregulation of CD73 ( NT5E ), an ectoenzyme and emerging immune checkpoint that generates extracellular adenosine, suggesting an adaptive mechanism that undermines olaparib efficacy and promotes immunosuppression. CD73 induction by olaparib was validated in human and mouse prostate cancer cell lines, with more pronounced effects in HRR-compromised PTEN-KO cells. Mechanistically, olaparib-driven CD73 expression was mediated through DNA damage–activated ATR/CHEK1/IRF1 and TGF-β1/AKT signaling pathways. In parallel, olaparib enhanced tumor immunogenicity by activating type I IFN signaling and antigen presentation machinery. In vivo, combining olaparib with CD73 blockade significantly delayed tumor growth, improved T cell infiltration, and augmented CD8 ⁺ T cell effector function across HRR-proficient and PTEN-KO prostate cancer models. These findings identify olaparib-induced CD73 upregulation as an adaptive resistance mechanism and support olaparib plus CD73 blockade as a promising therapeutic strategy for advanced prostate cancer, irrespective of HRR status.

Glioblastoma, IDH-wildtype (GBM, WHO grade 4) is the most common malignant glioma in adults and is characterized by a hypoxic and immunosuppressive tumor microenvironment (TME). Bone marrow-derived tumor-associated macrophages (TAMs) dominate the immune landscape in GBM and are recruited to the peri-necrotic niche following the onset of necrosis. CLEC5A has the strongest association with poor clinical outcome among immune-related genes in GBM, and is preferentially expressed in hypoxic, peri-necrotic TAMs. CLEC5A overexpression promotes TAM polarization toward an immunosuppressive phenotype, and secretion of immunoregulatory cytokines. Using an RCAS/tv-a GBM model with bone marrow transplantation from Clec5a ^-/- donor mice, we demonstrated that CLEC5A loss prolongs survival, delays tumor progression, and attenuates TME immunosuppression. Mechanistically, podoplanin (PDPN) expressed on glioma cells directly engages CLEC5A and triggers downstream Syk-JAK-STAT3 signaling in TAMs. Pharmacologic Syk inhibition suppresses glioma growth, diminishes TAM infiltration and polarization, reverses the immunosuppressive TME, and prolongs survival in vivo . Collectively, our findings indicate that the PDPN-CLEC5A-Syk-STAT3 axis orchestrates TAM polarization and TME immunosuppression in the peri-necrotic niche of GBM, highlighting CLEC5A/Syk as a promising therapeutic target for reversing the immunosuppressive TME and improving outcomes.

Immune checkpoint blockade (ICB), including PD-1/PD-L1 inhibitors, has transformed cancer therapy but benefits only a subset of patients. Understanding how PD-L1 is regulated and identifying strategies to overcome resistance remain critical. Here, we identify SIRT2 as a key positive regulator of PD-L1 across multiple human cancers. Unexpectedly, SIRT2 does not act at the transcriptional level but stabilizes PD-L1 protein by preventing ubiquitin-mediated degradation. Mechanistically, SIRT2 maintains the protein stability of USP22, a PD-L1 deubiquitinase. Loss of SIRT2 reduces USP22 levels, whereas ectopic USP22 fully rescues PD-L1 expression and reverses the enhanced antitumor immunity induced by SIRT2 inhibition. We further show that SIRT2 directly deacetylates USP22 at lysines 382 and 505 within its catalytic domain, promoting USP22 deubiquitinase activity and protecting both itself and its substrates from degradation. Our findings reveal a molecular mechanism by which an acetylation–deacetylation switch dynamically regulates deubiquitinase catalytic activity. Therapeutically, SIRT2 inhibition synergizes with PD-1/PD-L1 blockade and USP22 inhibition to enhance antitumor immunity. Consistently, protein but not mRNA levels of SIRT2, USP22, and PD- L1 positively correlate in human bladder cancer and melanoma. Together, these findings define a SIRT2–USP22–PD-L1 axis driving tumor immune evasion and highlight SIRT2 as a promising target to improve ICB efficacy.

Using over 100 intestinal tissue sections from non-diseased controls and patients with ulcerative colitis or Crohn’s disease across multiple inflammatory bowel disease consortia, we construct a spatially resolved atlas containing over three million cells and systematically evaluate two imaging-based spatial transcriptomics platforms. Here we show that CosMx tends to achieve higher detection efficiency than Xenium across commercially available panels in both ulcerative colitis and Crohn’s disease, whereas Xenium shows reduced performance associated with tissue type, block quality, and panel size. CosMx identifies regulatory T cell associated biology in both disease subtypes, which we validate using independent laboratory experiments and multi-plex spatial multi-omics. CosMx’s data quality remains stable across variation in fixation time and sectioning procedures, supporting its operational feasibility for multi-center studies. This study establishes a technical and biological benchmark for the application of single-cell-resolved spatial transcriptomics in gastrointestinal tissue, enabling more reliable application of spatial technologies in translational inflammatory bowel disease research.

Regulatory T cells (Tregs) are central mediators of immune tolerance, yet within tumors they adopt specialized phenotypes that confer the potent suppression of anti-tumor immune responses. Emerging evidence indicates that this functional plasticity is not driven by genetic alterations but instead arises from dynamic and context-dependent epigenetic reprogramming. While individual epigenetic mechanisms controlling Treg development and stability have been described, how tumor-derived cues reshape Treg epigenetic states, how these programs differ across cancer types, and which features distinguish tumor-infiltrating Tregs from their peripheral counterparts remain incompletely understood. In this review, we synthesize recent advances in DNA methylation, histone modifications, chromatin accessibility, and non-coding RNA regulation that govern Treg identity and function with a particular emphasis on tumor-specific epigenetic adaptations. We highlight emerging epigenetic hallmarks of intratumoral Tregs, discuss unresolved mechanistic questions, and evaluate the therapeutic potential and limitations of targeting epigenetic pathways to selectively modulate Tregs in cancer. By integrating mechanistic, cancer-specific, and translational perspectives, this review aims to provide a conceptual framework for understanding how epigenetic regulation shapes Treg behavior in the tumor microenvironment and how it may be exploited for cancer immunotherapy.

Hepatic lipid metabolism is regulated by circadian rhythms and dynamically responds to nutrient availability, such that lipid synthesis, oxidation, and storage are temporally coordinated. We demonstrated that the endoplasmic reticulum (ER)–localized E3 ubiquitin ligase HRD1 stimulated lipid accumulation in the liver by decreasing the N ⁶ -methyladenosine (m6A) methylation and expression of mRNAs encoding factors involved in lipid metabolism. In mouse livers, m6A RNA modification and the expression of mRNAs encoding the m6A writer METTL14 and the m6A reader YTHDF3 were under circadian control and inversely correlated with the abundance of HRD1. m6A RNA sequencing analyses revealed that HRD1 and the m6A writer METTL14 had opposing roles in the m6A modification and expression of mRNAs encoding factors involved in fatty acid metabolism. In vivo, hepatic lipid accumulation and triglyceride amounts were decreased in mice with hepatic HRD1 deficiency fed a high-fat diet but increased in mice with hepatic METTL14 or YTHDF deficiency fed normal chow. Mechanistically, HRD1 mediated the polyubiquitination and degradation of PPARα, which transcriptionally activated METTL14 and YTHDF3 expression in the liver. Our work identifies a pathway regulated by circadian rhythms or nutrients in which HRD1 promotes the degradation of PPARα to decrease the m6A modification and expression of hepatic mRNAs encoding factors involved in lipid metabolism.