Glycometabolic reprogramming-induced XRCC1 lactylation confers therapeutic resistance in ALDH1A3-overexpressing glioblastoma The prognosis for patients with GBM remains bleak. Understanding the mechanisms in these patients is crucial for the development of new treatments. In this paper, they find patients with high ALDH1A3-expressing glioblastoma (ALDH1A3hi GBM) show limited benefit from postoperative chemoradiotherapy. Next, they confirm that ALDH1A3-mediated tetramerization of PKM2 induces glycometabolic reprogramming in GSCs and XRCC1 undergoes lactylation at lysine 247 (K247) in lactate-accumulating GSCs. The lactylation of XRCC1 improves DNA repair via its increased nuclear localization. Through high-throughput screening of a small-molecule library, they show that D34-919 potently disrupts the ALDH1A3-PKM2 interaction, preventing the ALDH1A3-mediated enhancement of PKM2 tetramerization. Together, their findings show that D34-919 provides a new therapeutic option for patients with ALDH1A3hi GBM. DOI: 10.1016/j.cmet.2024.07.011.
Immunotherapy-activated T cells recruit and skew late-stage activated M1-like macrophages that are critical for therapeutic efficacy![]()
Marit J. van Elsas et al.
Most of these therapies for many cancer types are focused on the T cell compartment. Total tumor clearance through immunotherapy is associated with a fully coordinated innate and adaptive immune response. In this paper, they demonstrate that immunotherapy-induced CD8+ T cells summon macrophages via CCR5 signaling and activated T cells skew macrophages into late-stage activated M1-like macrophages. These macrophages play a crucial role in effective tumor control in mouse models and are correlated to clinical responses in humans. The requirement of a functional co-operation between CD8+ T cells and effector macrophages for effective immunotherapy gives warning to combinations with broad macrophage-targeting strategies.
DOI: 10.1016/j.ccell.2024.04.011.
Editor & Reviewer: Yanwen Wang
