A Kla-high transcriptional signature shortens median overall survival by 18 months and stratifies patients with poor response to sorafenib and immune checkpoint blockade. Three convergent therapeutic entry points emerge: depletion of lactate via glycolytic inhibition or MCT1/4 blockade (FX11, AZD3965), enzymatic modulation of Kla writers or erasers, and PROTAC-mediated degradation of oncogenic lactylated proteins. In murine and patient-derived xenograft models, these strategies reduce tumour volume by at least 50% and synergise durably with anti-PD-1 therapy. This integrated synthesis positions lysine lactylation as a hierarchical regulator that links metabolic stress to epigenetic plasticity, immune escape, and therapeutic vulnerability, and outlines a biomarker-driven roadmap for lactylation-targeted precision medicine in HCC.

We elucidate a Kla-dependent mechanism underlying GCMSCs-mediated ECM remodeling and immunosuppressive niche formation. The results provide novel insights into the epigenetic regulation of immunosuppressive TME.

Furthermore, pharmacological studies revealed that metformin combined with copanlisib significantly inhibited tumors by blocking the energy metabolism pathways PI3K/AKT and AMPK/mTOR. Rationally, targeting multiple nodes along the ENO1-ATP/lactate-AMPK/PI3K/AKT-mTOR axis may be effective for GC treatment, as indicated by the significant suppression of tumor growth by metformin (which inhibits ATP production) plus syrosingopine (which disrupts lactate homeostasis). In conclusion, the complex interplay between metabolism and tumor stemness offers novel therapeutic directions and potential treatment strategies for GC.

Combinational therapy using MCT1 inhibitors (e.g. AZD3965), MCT4 inhibitors and immune checkpoint blockade can suppress lactate-mediated immunosuppression in the TME. By disrupting lactate shuttling between glycolytic and oxidative tumour cells, this strategy promotes T cell function and improves cancer treatment outcomes.

Herein, exogenous lactate induced a pro-tumorigenic phenotype in BM-MSCs, which was blocked by AZD3965...Collectively, gastric cancer cells induce an iCAF-like phenotype and function in BM-MSCs through a lactate shuttle mechanism, emphasizing the role of metabolic reprogramming in cellular communication that fosters a supportive tumor microenvironment. Targeting lactate-related pathways may provide new therapeutic strategies to hinder BM-MSCs' supportive roles in gastric cancer.

Furthermore, we showed that the combination therapy of targeting PD-L1 with our PD-L1 antibody-drug conjugate (PD-L1-ADC) and reducing lactic acid with the monocarboxylate transporter 1 (MCT-1) inhibitor, AZD3965, can effectively treat the PD-1/PD-L1 blockade-resistant tumors. The findings of this study provide a new mechanism of how lactic acid induces an immunosuppressive tumor microenvironment and suggest a potential combination treatment to overcome the tumor resistance to PD-1/PD-L1 blockade therapy.

The results indicated the role of MCT1/4 in the pathobiology of GBM and the diagnostic utility at the immunohistochemical level. Syrosingopine, an antihypertensive agent with good CNS penetration and previously used in different malignancies, may be an essential therapeutic adjunct in GBM.

Elevated lactate level in PIG1-conditioned medium (PIG1-CM) induced M2 polarization, whereas the lactate transport inhibitor AZD3965 suppressed this effect in PBMCs cultured with A375-CM...Significantly, polarized macrophages altered melanoma phenotypes including proliferation, clone formation, cell cycle, apoptosis, migration and invasion via TCA cycle and TGF-β. Our data collectively demonstrate that lactate derived from melanoma facilitates polarization of M2 macrophages, which subsequently leads to modifications in melanoma phenotypes via TCA cycle and TGF-β signaling.

In conclusion, our results unveil lactate as a key regulator of immune escape and BM fibrotic transformation in MF patients, suggesting MCT1 blocking as a novel antifibrotic strategy.

P1/2, N=169, Completed, Cyteir Therapeutics, Inc. | Active, not recruiting --> Completed | Trial completion date: Apr 2025 --> Dec 2024

In vivo experiments had shown that emodin and AZD3965 could effectively inhibit the growth of lung cancer and inhibit the expression of MCT1. All in all, our data suggested that emodin inhibited the proliferation, migration, and invasion of lung cancer cells, possibly by inhibiting MCT1, providing important theoretical basis for elucidating the mechanism of emodin in treating lung cancer.

P1/2, N=170, Active, not recruiting, Cyteir Therapeutics, Inc. | Trial completion date: Dec 2024 --> Apr 2025 | Trial primary completion date: Jul 2024 --> Dec 2024