IKZF2 (IKAROS family zinc finger 2)

SCENIC analysis revealed HAND2, IKZF2 and SOX10 as transcriptional regulators of human NGFR+ antigen-presenting TAS cells, and they frequently expressed enteric glial cell markers SOX10, PLP1, CDH19 and NCAM1. In summary, our study demonstrates that the frequency and spatial distribution of TAS subpopulations, particularly NGFR+ TAS organization within TLS, varies between CRC patients and correlates with DFS and distinct changes in the TME.

Our findings support the utility of methylome-wide cfDNA profiling for LC biomarker discovery. EMP2 promoter methylation represents a promising candidate for the minimally invasive detection of LC across heterogeneous clinical presentations.

Stool Fibrinogen, MMP-8, MMP-9, PGRP-S, Haptoglobin, and Myeloperoxidase emerge as promising biomarkers for distinguishing CRC/advanced adenomas/healthy stools, meeting or outperforming current yardsticks.

Functionally, reprogrammed DCs employed distinct immune mechanisms to elicit orthogonal anti-tumor responses in different tumor models. Collectively, our findings uncover transcriptional circuits that control DC diversification and pave the way to generate patient-tailored DC subsets for cancer immunotherapy.

We developed a novel series of iso-indolinone-based glutarimides, identifying compound 55 as a potent, selective IKZF2 degrader with >90% Dmax in Jurkat cells, outperforming benchmarks DKY709 and PVTX-405. PK/PD studies confirmed profound, persistent IKZF2 degradation in mouse spleen and thymus after a single oral dose. As a promising early-stage tool, 55 provides a foundation for further preclinical evaluation in cancer immunotherapy.

Moreover, IKZF2 knockout hindered the accumulation of aberrant stem cells driven by AML1-ETO and promoted cellular differentiation both in vitro and in vivo. These facilitate a better understanding of the leukaemia cell heterogeneity in t(8;21) AML and unveil IKZF2 as a potential target for improving current treatment strategies.

These features are coupled with a unique transcription factor landscape, including high expression of thymocyte selection associated high mobility group box (TOX) and HELIOS (IKZF2), and these signatures continue in postnatal life until at least 2 mo of age. We conclude that early-life human CD8+ T cells maintain a unique transcriptional state associated with an accelerated effector switch and short-lived effector program, revealing key nodes of regulation relevant for the unique immunobiology of neonatal humans.

Hence, this study presents an optimized cancer vaccine that cures most tumor-bearing mouse models and the landscape of immune cells in non-responders and responders to immunotherapy. The results of this study will help to develop better cancer vaccines.

Compared with normal breast epithelium cells, RFX5, VEGFA were upregulated in breast cancer cells, IKZF2, NAB1, S100B were downregulated in breast cancer cells while F2R, S1PR2 showed no significance. We established a seven-gene immune-related signature for predicting lymph node metastasis in BC, which might provide a novel sight for BC diagnosis and treatment.

We illustrate the profound reprogramming of the liver immune microenvironment in the MASH-to-HCC transition and clarify the role of ApoE in MASH-driven HCC, implying that ApoE may serve as a potential therapeutic target for MASH-related HCC.

Our findings highlight the feasibility of developing precise IKZF2 degraders and provide a framework for optimizing selectivity in molecular glue design, offering a potential therapeutic strategy for IKZF2-dependent cancers. 2025 Elsevier Ltd.

Furthermore, our high-throughput screening identified novel candidates from extensive chemical libraries, validated through advanced FEP+ simulations. This study not only underscores the transformative potential of molecular glues in targeted protein degradation but also sets the stage for their broader application across diverse protein targets, paving the way for innovative therapeutic strategies in drug discovery.