免疫检查点阻滞(ICB)对癌症可以产生持久的治疗效果。我们和其他人发现一部分患者在免疫疗法期间出现了自相矛盾的快速癌症进展。肿瘤如何在免疫检查点阻滞期间加速其进展还没有得到深入的了解。在某些临床前模型中，ICB会引起高速进展性疾病(HPD)。免疫排斥导致ICB的抗性，在患有HPD和完全缓解(CR)的患者中，肿瘤浸润的CD8+ T细胞和干扰素γ(IFNγ)基因签名的水平相似，这是出乎意料的。有趣的是，患有HPD但无CR的患者表现出提高的肿瘤成纤维细胞生长因子2(FGF2)和β-连环素信号。在动物模型中，T细胞源性IFNγ促进肿瘤FGF2信号，从而抑制PKM2活性，降低NAD+，导致降低SIRT1介导的β-连环素去乙酰化和增强β-连环素乙酰化，进而重编程肿瘤干细胞状态。靶向IFNγ-PKM2-β-连环素轴可预防临床前模型中的HPD。因此，IFNγ-PKM2-β-连环素级联通过核心免疫原型、代谢和致癌通路的交互作用形成了ICB相关的HPD。版权所有© 2022 Elsevier Inc.

Immune checkpoint blockade (ICB) can produce durable responses against cancer. We and others have found that a subset of patients experiences paradoxical rapid cancer progression during immunotherapy. It is poorly understood how tumors can accelerate their progression during ICB. In some preclinical models, ICB causes hyperprogressive disease (HPD). While immune exclusion drives resistance to ICB, counterintuitively, patients with HPD and complete response (CR) following ICB manifest comparable levels of tumor-infiltrating CD8+ T cells and interferon γ (IFNγ) gene signature. Interestingly, patients with HPD but not CR exhibit elevated tumoral fibroblast growth factor 2 (FGF2) and β-catenin signaling. In animal models, T cell-derived IFNγ promotes tumor FGF2 signaling, thereby suppressing PKM2 activity and decreasing NAD+, resulting in reduction of SIRT1-mediated β-catenin deacetylation and enhanced β-catenin acetylation, consequently reprograming tumor stemness. Targeting the IFNγ-PKM2-β-catenin axis prevents HPD in preclinical models. Thus, the crosstalk of core immunogenic, metabolic, and oncogenic pathways via the IFNγ-PKM2-β-catenin cascade underlies ICB-associated HPD.Copyright © 2022 Elsevier Inc. All rights reserved.