PDF(Pubmed)
Abstract：
Mismatch repair proficient (MMRp) tumors of colorectal origin are one of the prevalent yet unpredictable clinical challenges. Despite earnest efforts, optimal treatment modalities have yet to emerge for this class. The poor prognosis and limited actionability of MMRp are ascribed to a low neoantigen burden and a desert-like microenvironment. This review focuses on the critical roadblocks orchestrated by an immune evasive mechanistic milieu in the context of MMRp. The low density of effector immune cells, their weak spatiotemporal underpinnings, and the high-handedness of the IL-17-TGF-β signaling are intertwined and present formidable challenges for the existing therapies. Microbiome niche decorated by Fusobacterium nucleatum alters the metabolic program to maintain an immunosuppressive state. We also highlight the evolving strategies to repolarize and reinvigorate this microenvironment. Reconstruction of anti-tumor chemokine signaling, rational drug combinations eliciting T cell activation, and reprograming the maladapted microbiome are exciting developments in this direction. Alternative vulnerability of other DNA damage repair pathways is gaining momentum. Integration of liquid biopsy and ex vivo functional platforms provide precision oncology insights. We illustrated the perspectives and changing landscape of MMRp-CRC. The emerging opportunities discussed in this review can turn the tide in favor of fighting the treatment dilemma for this elusive cancer.
摘要：
结肠直肠起源的错配修复（MMRp）肿瘤是普遍但不可预测的临床挑战之一。尽管认真努力，这一类的最佳治疗方式尚未出现。MMRp的不良预后和有限的可操作性归因于低的新抗原负荷和沙漠样的微环境。这篇评论的重点是在MMRp的背景下由免疫规避机制环境精心安排的关键路障。效应免疫细胞的低密度，它们微弱的时空基础，IL-17-TGF-β信号的高压交织在一起，对现有疗法提出了严峻的挑战。由核梭杆菌修饰的微生物组生态位改变了代谢程序以维持免疫抑制状态。我们还强调了不断发展的战略，以重新极化和重振这种微环境。抗肿瘤趋化因子信号的重建，诱导T细胞活化的合理药物组合，重新编程适应不良的微生物组是这个方向上令人兴奋的发展。其他DNA损伤修复途径的替代脆弱性正在获得动力。液体活检和离体功能平台的整合提供了精确的肿瘤学见解。我们说明了MMRp-CRC的观点和不断变化的格局。这篇评论中讨论的新兴机会可以扭转潮流，有利于解决这种难以捉摸的癌症的治疗困境。
