Mechanisms of systemic immune modulation in tumor development: Interactions across lymph nodes, bone marrow, and blood.

Cancer is a systemic disease in which the tumor interacts with the entirety of the body to promote tumor pathogenesis and progression. While tremendous efforts have focused on understanding the local immune responses in the primary site because of the noticeable immunosuppressive characteristics in the tumor microenvironment (TME), the interaction between the tumor and the host's systemic response has not received much attention. These interactions influence primary tumor growth and treatment responses and can further facilitate tumor dissemination and condition distant tissues for metastatic colonization. In this review, we summarize the reciprocal interactions between the primary tumor and the systemic environment throughout cancer development, including pre-metastatic niche formation and metastatic progression, with particular emphasis on tumor-draining lymph nodes (TDLNs), bone marrow (BM), and blood circulation. By integrating these perspectives, this review aims to provide a more comprehensive understanding of tumor development within the whole-body context, thereby highlighting the development and optimization of strategies in cancer diagnosis, prognosis, and treatment that account for the systemic nature of the disease.