Faculty Bibliography

Therapeutic resistance remains the principal barrier to durable clinical benefit in oncology, particularly in oncogene-driven malignancies and immune-refractory tumors. This meeting brought together leading experts to dissect the multifaceted biological mechanisms underlying drug tolerance, adaptive resistance, and immune escape across diverse cancer types. Presentations highlighted how cancer cell-intrinsic plasticity, chromatin reprogramming, and stress-responsive transcriptional networks intersect with tumor microenvironment-derived cues, including inflammatory signaling, stromal heterogeneity, mechanotransduction, and paracrine crosstalk, to sustain drug-tolerant persister states. Novel insights into cancer-associated fibroblast plasticity, spatially organized immunosuppressive niches, secretory autophagy, and senescence-associated programs underscored the dynamic and adaptive nature of resistance. Cutting-edge approaches, including single-cell and spatial transcriptomics, chromatin accessibility profiling, organoid-based co-culture platforms, and artificial intelligence-driven spatial inference, revealed actionable vulnerabilities and predictive biomarkers. Collectively, these studies emphasize that resistance is not a binary phenomenon but a continuum shaped by evolutionary adaptation and ecological interactions within the TME. This report synthesizes the conceptual advances and translational implications emerging from the meeting, outlining new therapeutic strategies aimed at disrupting adaptive tolerance states, reprogramming immunosuppressive niches, and enabling fast, accessible precision oncology.

Therapeutic resistance remains the principal barrier to durable clinical benefit in oncology, particularly in oncogene-driven malignancies and immune-refractory tumors. This meeting brought together leading experts to dissect the multifaceted biological mechanisms underlying drug tolerance, adaptive resistance, and immune escape across diverse cancer types. Presentations highlighted how cancer cell-intrinsic plasticity, chromatin reprogramming, and stress-responsive transcriptional networks intersect with tumor microenvironment-derived cues, including inflammatory signaling, stromal heterogeneity, mechanotransduction, and paracrine crosstalk, to sustain drug-tolerant persister states. Novel insights into cancer-associated fibroblast plasticity, spatially organized immunosuppressive niches, secretory autophagy, and senescence-associated programs underscored the dynamic and adaptive nature of resistance. Cutting-edge approaches, including single-cell and spatial transcriptomics, chromatin accessibility profiling, organoid-based co-culture platforms, and artificial intelligence-driven spatial inference, revealed actionable vulnerabilities and predictive biomarkers. Collectively, these studies emphasize that resistance is not a binary phenomenon but a continuum shaped by evolutionary adaptation and ecological interactions within the TME. This report synthesizes the conceptual advances and translational implications emerging from the meeting, outlining new therapeutic strategies aimed at disrupting adaptive tolerance states, reprogramming immunosuppressive niches, and enabling fast, accessible precision oncology.

Inactivation of tumor suppressor genes (TSGs) imparts a cellular fitness in cancers, including in acute myeloid leukemia (AML). The detection of silenced TSGs without direct mutations presents challenges in designing targeted cancer treatments, yet it also opens a therapeutic opportunity to restore their function. In this study, we identified the transcriptional repressor ZBTB7A as a TSG that is down-regulated in samples from patients with AML and is associated with poor survival outcomes. Loss of ZBTB7A amplifies TNF signaling, driving a dysfunctional inflammatory state that accelerates AML progression in vivo. Mechanistically, the mRNA decay factor ZFP36L2 binds to the 3' untranslated region (3'UTR) of ZBTB7A, promoting its transcript degradation in human AML cells. To identify therapeutic targets, we developed a CRISPR-based screening approach coupled with fluorescence in situ hybridization and flow cytometry (FISH-Flow), pinpointing the KDM4 family of histone demethylases as a vulnerability to restore ZBTB7A function. Pharmacologic inhibition of KDM4 up-regulated ZBTB7A expression, promoted terminal differentiation in patient-derived xenograft models, and demonstrated broad antileukemic efficacy across AML subtypes as well as preserved normal hematopoiesis. These findings reveal regulatory mechanisms of ZBTB7A and support epigenetic therapy as a promising strategy to reactivate its tumor suppressor function in hematologic cancers.

Standard techniques for detecting genomic rearrangements in formalin-fixed paraffin-embedded (FFPE) biopsies have important limitations. We performed FFPE-compatible Hi-C on 44 clinical biopsies comprising large B cell lymphomas (n = 18), plasma cell neoplasms (n = 14), and other diverse lymphoid cancers, identifying consistent topological differences between malignant B cell and plasma cell states. Hi-C detected expected oncogene rearrangements at high concordance with fluorescence in situ hybridization (FISH) and supported enhancer hijacking in recurrent rearrangements of BCL2, CCND1, and MYC plus unanticipated variants involving homologous loci. Hi-C identified unanticipated non-coding rearrangements involving PD-1 ligand genes and other loci of potential therapeutic relevance, distinguished between functionally divergent classes of BCL6 rearrangements, and provided topological information supporting interpretation of variant MYC rearrangements. Hi-C revealed disease-selective MYC locus topological features that correlated with disease-selective MYC locus enhancers and rearrangement breakpoint distributions. FFPE-compatible Hi-C detects oncogene rearrangements and their topological consequences at genome-wide scale, finding clinically relevant drivers missed by standard approaches.

Cancer cells activate the integrated stress response (ISR) to adapt to stress and resist therapy¹. ISR signals converge on activating transcription factor 4 (ATF4), which controls cell-intrinsic transcriptional programs that are involved in metabolic adaptation, survival and growth^2,3. However, whether the ISR-ATF4 axis influences anti-tumour immune responses remains mostly unknown. Here we show that loss of ATF4 decreases tumour progression considerably in immunocompetent mice, but not in immunocompromised ones, by enhancing T cell-dependent anti-cancer immune responses. An unbiased genetic screen of ATF4-regulated genes identifies lipocalin 2 (LCN2) as the principal ATF4-dependent effector that impairs anti-tumour immunity by favouring infiltration with immunosuppressive interstitial macrophages. Furthermore, we find that LCN2 promotes T cell exclusion and immune evasion in preclinical mouse models, and correlates with decreased T cell infiltration in patients with lung and pancreatic adenocarcinomas. Anti-LCN2 antibodies promote robust anti-tumour T cell responses in mouse models of aggressive solid tumours. Our study shows that the ATF4-LCN2 axis has a cell-extrinsic role in suppressing anti-cancer immunity, and could pave the way for an immunotherapy approach that targets LCN2.

Dendritic cells (DCs) facilitate the maintenance of immunological tolerance in the steady state. We report that transcription factor Etv3 is preferentially expressed in mature DCs, including tissue-derived migratory DCs (migDCs), and facilitates their homeostatic maturation and CCR7-dependent migration. Mice with global or DC-specific deletion of Etv3 manifested the expansion of CD25^low regulatory T (T_reg) cells, spontaneous activation of conventional T cells, and multiorgan T cell infiltration. Etv3 deficiency exacerbated TLR7-driven systemic lupus erythematosus (SLE)-like disease, supporting the reported genetic association of human ETV3 with SLE. Etv3-deficient migDCs up-regulated multiple costimulatory molecules, including OX40 ligand (OX40L/TNFSF4), whose blockade partially rescued the T_reg cell abnormalities. These results identify Etv3 as an essential regulator of the tolerogenic function of DCs and implicate it in the regulation of human autoimmunity.

Type I interferons (IFN-I), including IFN-β and multiple IFN-α subtypes, are key antiviral proteins encoded within a single large locus. Here, we studied how the chromatin organization of this locus controls cell-type-specific IFN-I responses. The professional IFN-I-producing plasmacytoid dendritic cells (pDCs) simultaneously induced nearly all IFN-I subtypes across the locus. During pDC differentiation, the IFN-I locus translocated into the active intranuclear chromosomal compartment. It also underwent cohesin-dependent reorganization of its three-dimensional chromatin structure; accordingly, IFN-I production by pDCs was cohesin dependent. The promoters of most IFN-I genes harbored open chromatin peaks specifically in pDCs. The preemptive intranuclear translocation and promoter opening of IFN-I genes in pDCs were mediated by the pDC-enriched transcription factor interferon regulatory factor (IRF)8. Several IRF8- and/or cohesin-binding regulatory regions within the IFN-I locus facilitated IFN-I gene induction in pDCs, as confirmed by single-cell multiome analysis. Thus, the unique IFN-I-producing capacity of pDCs is facilitated by anticipatory chromatin organization imparted by IRF8 and cohesin.

The cohesin complex extrudes chromatin loops, stopping at sites bound by CCCTC-binding factor (CTCF) and organizing chromosomes into topologically associated domains, yet biological implications of this process remain obscure. We show that cohesin controls the in vivo differentiation and function of murine antigen-presenting dendritic cells (DCs), particularly antigen cross-presentation and interleukin-12 (IL-12) secretion by type 1 conventional DCs (cDC1s). The chromatin organization of DCs was shaped by cohesin and the transcription factor IRF8, which facilitated chromatin looping and chromosome compartmentalization, respectively. Optimal expression of IRF8 itself required CTCF/cohesin binding sites demarcating the Irf8 gene. During DC activation, cohesin enabled the induction of a subset of genes that were preferentially located in Polycomb-repressed regions and enriched in more distal enhancers. Accordingly, deletion of CTCF sites flanking the Il12b gene in mice reduced IL-12 production by cDC1s. Our data reveal an essential role of cohesin-mediated chromatin folding in cell differentiation and function in vivo and its bidirectional cross-talk with lineage-specifying transcription factors.

Chronic wounds, especially in diabetic patients, pose a significant clinical challenge due to impaired microvasculature and delayed healing. This study presents Exo-Q, a novel thermoresponsive hydrogel formed by co-gelation of engineered Q protein nanofibers with exosomes, a class of vesicular intercellular communication mediators. Exo-Q transitions from a gel to a viscoelastic solution at physiological temperature, enabling localized, topical delivery of exosomes with an initial burst release followed by sustained release. In a diabetic mouse wound model, Exo-Q effectively delivered human bone marrow multipotent stromal cell-derived exosomes directly to the wound bed, where they accumulated in endothelial cells of granulation tissue without detectable systemic distribution. Exosomes produced under stringent and replicable cell culture conditions consistently carried biomacromolecular cargo enriched for miRNAs with validated targets in angiogenesis-associated genes, indicative of their therapeutic potential. Topical application of Exo-Q resulted in extensive neovascularized granulation tissue, significantly accelerating wound closure to levels comparable to non-diabetic wounds. Importantly, the hydrogel's modular design maintained the functional integrity of Q protein nanofibers and exosomes, demonstrating compatibility with full-thickness human wounds. This platform allows for tailored customization to address critical stages of diabetic wound healing while ensuring efficacy at low dosages, potentially enabling patient-administered treatment. By leveraging advanced biomaterials, Exo-Q advances the therapeutic efficacy of exosome-based interventions for diabetic wounds, offering a localized, non-invasive solution to chronic, non-healing wounds. This innovative hydrogel platform represents a modular therapeutic strategy with significant potential for clinical applications in regenerative medicine.

Chronic wounds, especially in diabetic patients, pose a significant clinical challenge due to impaired microvasculature and delayed healing. This study presents Exo-Q, a novel thermoresponsive hydrogel formed by co-gelation of engineered Q protein nanofibers with exosomes, a class of vesicular intercellular communication mediators. Exo-Q transitions from a gel to a viscoelastic solution at physiological temperature, enabling localized, topical delivery of exosomes with an initial burst release followed by sustained release. In a diabetic mouse wound model, Exo-Q effectively delivered human bone marrow multipotent stromal cell-derived exosomes directly to the wound bed, where they accumulated in endothelial cells of granulation tissue without detectable systemic distribution. Exosomes produced under stringent and replicable cell culture conditions consistently carried biomacromolecular cargo enriched for miRNAs with validated targets in angiogenesis-associated genes, indicative of their therapeutic potential. Topical application of Exo-Q resulted in extensive neovascularized granulation tissue, significantly accelerating wound closure to levels comparable to non-diabetic wounds. Importantly, the hydrogel's modular design maintained the functional integrity of Q protein nanofibers and exosomes, demonstrating compatibility with full-thickness human wounds. This platform allows for tailored customization to address critical stages of diabetic wound healing while ensuring efficacy at low dosages, potentially enabling patient-administered treatment. By leveraging advanced biomaterials, Exo-Q advances the therapeutic efficacy of exosome-based interventions for diabetic wounds, offering a localized, non-invasive solution to chronic, non-healing wounds. This innovative hydrogel platform represents a modular therapeutic strategy with significant potential for clinical applications in regenerative medicine.