肾癌与肿瘤微环境相互作用及其潜在治疗策略 的研究进展

Research Progress on the Interaction between Renal Cancer and the Tumor Microenvironment and Its Potential Therapeutic Strategies

摘要: 肾透明细胞癌(ccRCC)是最常见的泌尿系统恶性肿瘤之一，约占成人恶性肿瘤的2%~3%，同时也是泌尿系统中致死率最高的癌种。ccRCC作为肾癌中最常见的一种亚型，具有发病隐匿、早期症状不典型的特点，导致多数患者在确诊时已发展至晚期，对于晚期患者而言，其死亡的主要原因通常涉及肾癌的广泛远处转移、严重并发症及多器官功能衰竭。ccRCC的演进与肿瘤微环境(TME)密切相关，二者之间的复杂相互作用对其增殖、侵袭和转移有着重大影响，如免疫肿瘤相关巨噬细胞，在机体中既能发挥抗肿瘤免疫，还能被诱导为促肿瘤状态，影响肾癌细胞的发生发展；缺氧等微环境变化还能影响癌细胞的代谢重编程，激活各项信号通路，影响免疫细胞的功能等。随着时代发展，免疫治疗及靶向治疗的大大改善了晚期肾透明细胞癌患者的预后，但几乎所有患者最终都会产生耐药。近年来，基于肿瘤微环境的免疫治疗，如免疫检查点抑制剂，靶向微环境中的细胞因子或血管生成因子展示出了广阔的应用前景。因此，深入研究肾透明细胞癌和肿瘤微环境的相互关系，有助于开发更有效的肾透明细胞癌治疗手段。本综述系统阐述了ccRCC中TME的组成(包括免疫细胞、基质细胞和细胞外基质)及其相互作用，并深入探讨了基于TME的治疗策略与潜在的免疫靶点。

Abstract: Clear cell renal cell carcinoma (ccRCC) is one of the most common malignant tumors of the urinary system, accounting for approximately 2% to 3% of adult malignancies, and it is also the most lethal cancer within the urinary system. As the most prevalent subtype of renal carcinoma, ccRCC is characterized by insidious onset and atypical early symptoms, leading to most patients being diagnosed at an advanced stage. For advanced-stage patients, the primary causes of death typically involve extensive distant metastasis, severe complications, and multi-organ failure. The progression of ccRCC is closely intertwined with the tumor microenvironment (TME). The complex interactions between these two entities profoundly influence tumor proliferation, invasion, and metastasis. For instance, tumor-associated macrophages (TAMs) within the body can exert anti-tumor immunity but may also be induced into a pro-tumor state, thereby impacting the development and progression of renal cancer cells. Microenvironmental alterations such as hypoxia can also influence cancer cell metabolic reprogramming, activate signaling pathways, and affect immune cell function. With advances in immunotherapy and targeted therapies, the prognosis for patients with advanced clear cell renal cell carcinoma has significantly improved. However, nearly all patients eventually develop resistance. In recent years, immunotherapies targeting the tumor microenvironment, such as immune checkpoint inhibitors and those targeting cytokines or angiogenesis factors within the microenvironment, have demonstrated broad application potential. Therefore, in-depth investigation of the interplay between renal clear cell carcinoma and its tumor microenvironment may facilitate the development of more effective therapeutic approaches. This review systematically outlines the composition of the TME in ccRCC (including immune cells, stromal cells, and extracellular matrix) and their interactions, while thoroughly exploring TME-based therapeutic strategies and potential immune targets.