Decades of advancements in immuno-oncology have enabled the development of current immunotherapies, which provide long-term treatment responses in certain metastatic cancer patients. However, cures remain infrequent, and most patients ultimately succumb to treatment-refractory metastatic disease. Recent insights suggest that tumors at certain organ sites exhibit distinctive response patterns to immunotherapy and can even reduce antitumor immunity within anatomically distant tumors, suggesting the activation of tissue-specific immune tolerogenic mechanisms in some cases of therapy resistance. Specialized immune cells known as regulatory T cells (Tregs) are present within all tissues in the body and coordinate the suppression of excessive immune activation to curb autoimmunity and maintain immune homeostasis. Despite the high volume of research on Tregs, the findings have failed to reconcile tissue-specific Treg functions in organs, such as tolerance, tissue repair, and regeneration, with their suppression of local and systemic tumor immunity in the context of immunotherapy resistance. To improve the understanding of how the tissue-specific functions of Tregs impact cancer immunotherapy, we review the specialized role of Tregs in clinically common and challenging organ sites of cancer metastasis, highlight research that describes Treg impacts on tissue-specific and systemic immune regulation in the context of immunotherapy, and summarize ongoing work reporting clinically feasible strategies that combine the specific targeting of Tregs with systemic cancer immunotherapy. Improved knowledge of Tregs in the framework of their tissue-specific biology and clinical sites of organ metastasis will enable more precise targeting of immunotherapy and have profound implications for treating patients with metastatic cancer.

免疫肿瘤学数十年的进步使当前免疫疗法的发展成为可能，这些疗法可为某些转移性癌症患者提供长期的治疗反应。然而，治愈仍然很少，大多数患者最终死于治疗难治性转移性疾病。最近的见解表明，某些器官部位的肿瘤对免疫治疗表现出独特的反应模式，甚至可以降低解剖学上远处肿瘤内的抗肿瘤免疫，这表明在某些治疗抵抗的情况下激活了组织特异性免疫耐受机制。称为调节性 T 细胞 (Tregs) 的专门免疫细胞存在于身体的所有组织中，并协调抑制过度免疫激活以抑制自身免疫和维持免疫稳态。尽管对 Treg 进行了大量研究，但这些发现未能协调器官中组织特异性 Treg 的功能，例如耐受性、组织修复和再生，以及它们在免疫治疗耐药性的背景下抑制局部和全身肿瘤免疫。为了加深对 Tregs 的组织特异性功能如何影响癌症免疫治疗的理解，我们回顾了 Tregs 在临床常见和具有挑战性的癌症转移器官部位中的特殊作用，重点介绍了 Treg 对组织特异性和全身免疫调节的影响的研究。免疫疗法的背景，并总结正在进行的工作，报告临床上可行的策略，将 Tregs 的特异性靶向与全身性癌症免疫疗法相结合。