Renal cell carcinoma (RCC) is a biologically heterogeneous malignancy accounting for 3% of adult cancers globally. Despite advances in immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor (VEGF)-targeted therapies, durable disease control remains elusive for many patients. Increasing evidence implicates the acidic tumour microenvironment (TME) as a critical mediator of RCC progression, immune evasion, and therapeutic resistance. Solid tumours, including RCC, exhibit reversed pH gradients, characterised by acidic extracellular (pH 6.2–6.9) and alkaline intracellular conditions. This dysregulation arises from enhanced glycolysis, hypoxia-driven lactate accumulation, and the overexpression of pH-regulating enzymes such as carbonic anhydrase (CA9). Acidic TMEs impair cytotoxic T-cell and NK-cell activity, promote tumour-associated macrophage (TAM) polarisation towards an immunosuppressive phenotype, and upregulate alternative immune checkpoints. These mechanisms collectively undermine ICI efficacy and contribute to primary and secondary treatment resistance. Proton-sensing G-protein-coupled receptors (GPCRs), notably GPR65, have emerged as pivotal mediators linking extracellular acidosis to immune dysfunction. Preclinical studies demonstrate that GPR65 antagonists restore anti-tumour immune activity by reversing acidosis-driven immunosuppression and enhancing antigen processing. In RCC models, selective GPR65 inhibitors have shown the ability to reduce immunosuppressive cytokine IL-10 production, induce immunoproteasome activation, and synergise with anti-PD-1 therapy. The first-in-class GPR65 inhibitor, PTT-4256, is now under evaluation in the Phase I/II RAISIC-1 trial (NCT06634849) in solid tumours, including RCC. Targeting acid-sensing pathways represents a novel and promising therapeutic strategy in RCC, aiming to remodel the TME and overcome ICI resistance. Integrating GPR65 inhibition with existing immunotherapies may define the next era of RCC management, warranting continued translational and clinical investigation.
肾细胞癌（RCC）是一种生物学异质性恶性肿瘤，占全球成人癌症的3%。尽管免疫检查点抑制剂（ICIs）和血管内皮生长因子（VEGF）靶向治疗取得了进展，但对许多患者而言，持久的疾病控制仍难以实现。越来越多的证据表明，酸性肿瘤微环境（TME）是RCC进展、免疫逃逸和治疗耐药的关键介质。包括RCC在内的实体瘤表现出反向的pH梯度，其特征是细胞外酸性（pH 6.2–6.9）和细胞内碱性状态。这种失调源于糖酵解增强、缺氧驱动的乳酸积累以及碳酸酐酶（CA9）等pH调节酶的过度表达。酸性TME会损害细胞毒性T细胞和NK细胞的活性，促进肿瘤相关巨噬细胞（TAM）向免疫抑制表型极化，并上调替代性免疫检查点。这些机制共同削弱了ICI的疗效，并导致原发性和继发性治疗耐药。质子感应G蛋白偶联受体（GPCRs），特别是GPR65，已成为连接细胞外酸中毒与免疫功能障碍的关键介质。临床前研究表明，GPR65拮抗剂可通过逆转酸中毒驱动的免疫抑制和增强抗原加工来恢复抗肿瘤免疫活性。在RCC模型中，选择性GPR65抑制剂已显示出减少免疫抑制性细胞因子IL-10产生、诱导免疫蛋白酶体活化以及与抗PD-1疗法协同作用的能力。首创GPR65抑制剂PTT-4256目前正在针对包括RCC在内的实体瘤的I/II期RAISIC-1试验（NCT06634849）中进行评估。靶向酸感应通路是RCC中一种新颖且有前景的治疗策略，旨在重塑TME并克服ICI耐药。将GPR65抑制与现有免疫疗法相结合，可能定义RCC管理的下一个时代，值得继续进行转化和临床研究。
肿瘤(癌症)患者之家