PTPN2 (Protein Tyrosine Phosphatase Non-Receptor Type 2)

In preclinical models, the administration of Def-LNP@mRNATCPTP successfully eliminated steatohepatitis, impeded hepatocarcinogenesis, and improved the therapeutic responsiveness of HCC to cancer vaccine and immune checkpoint blockade therapy. Def-LNP@mRNATCPTP represents a potential therapeutic strategy for MAFLD and MAFLD-related HCC, potentially offering treatment paradigms for immunotherapy for HCC and metabolic liver diseases.

It enhanced lymphocyte infiltration into tumors and modulated IFN-γ signaling pathways. These findings indicate that compound K-38 is a potent small molecule inhibitor of PTPN2, laying the groundwork for the future development of PTPN2-targeted therapeutics.

Flow cytometric analysis reaffirmed that the deletion or inhibition of PTPN2 promoted the intratumoral accumulation of SCM CD8+ CAR T cells and the overall persistence of CD8+ CAR T cells. These data support the use of gene editing or small-molecule inhibitors targeting PTPN2 in human CAR T cells to treat solid tumors.

Furthermore, we demonstrate that phosphotyrosine mimetic inhibitors of PTPN1, which were already found to be safe in humans, can be repurposed for cancer immunotherapy. This strategy can be used to increase the efficacy of PD-1 blockade and broaden its use to other cancer types.

This strategy remodels the TME by activating cGAS-STING signaling and dual immune checkpoints blockade, thus realizing tumor elimination. Our theranostic nanomachine armed with the CRISPR-Cas9/DNAzyme logic systems, represents a resourceful and promising strategy for advancing cancer systemic immunotherapy and precise gene therapy.

In B16-OVA syngeneic models, WS35 monotherapy and its combination with an anti-PD-1 antibody achieved robust tumor growth suppression, outperforming AC484, with no observable systemic toxicity. Collectively, WS35 represents a preclinical candidate with validated efficacy and safety for developing novel antimelanoma therapeutics.

Mechanistically, PTPN2 maintains epithelial cell characteristics by upregulating E-cadherin while suppressing mesenchymal markers Snail and Twist through negative regulation of ERK1/2 phosphorylation. Our findings not only expand the current understanding of PTPN2's role in cancer biology but also suggest its dual potential as both a prognostic biomarker and a promising therapeutic target for OC treatment.

This study details the comprehensive evaluation of PTPN2-KO CAR-T cells in an immunocompetent model, demonstrating their enhanced on-target functionality, while highlighting increased toxicity risks, underscoring the need for rigorous preclinical assessment of potent genetic modifications in CAR-T therapy. PTPN2-KO CAR-T cells exhibit enhanced effector functionIn a dose escalation study in rhesus macaques, PTPN2-KO mediated enhanced proliferation and CNS infiltration was associated with increased ICANS.

CDKN1B ablation increased CAR T cell proliferation and effector function, significantly enhancing tumour clearance and overall survival. Our findings reveal differing effects of gene perturbation on CAR T cells over time and in different environments, highlight CDKN1B as a promising target to generate highly effective CAR T cells for multiple myeloma and underscore the potential of in vivo screening for identifying genes to enhance CAR T cell efficacy.

P1/2, N=26, Recruiting, Princess Maxima Center for Pediatric Oncology | Trial completion date: Oct 2031 --> Feb 2032 | Not yet recruiting --> Recruiting | Trial primary completion date: Oct 2031 --> Feb 2032

Additionally, our findings highlight the complex dynamics and interplay of cytokines, PTPs and metabolic pathways. This should be acknowledged when new therapeutic tools are developed to address inflammation-induced diseases such as type 2 diabetes or related comorbidities.

Interestingly, TFRC is directly regulated by the transcription factor hypoxia-inducible factor 1 alpha (HIF1A) in its promoter. Notably, an orally bioavailable potent PTPN2/N1 active-site inhibitor ABBV-CLS-484 (AC484) demonstrates significant therapeutic potential against ALK+ ALCL by disturbing mitochondrial renewal and blocking TFRC-mediated PINK1-PRKN-dependent mitophagy to exert anti-tumor activities, providing critical insights into the selection of targeted treatment strategies for ALK+ ALCL patients and a strong rationale for advancing AC484 into clinical trials.