Tissue-resident immune cells in tumors: Cytokine-mediated regulation, functional plasticity, and therapeutic opportunities.

Traditional tumor immunology research has predominantly focused on circulating recruited immune cells. In contrast, tissue-resident immune cells-a unique subset that stably resides in normal tissues and the tumor microenvironment (TME) for extended periods without entering the systemic circulation-exhibit distinct transcriptional, epigenetic and functional profiles, and their roles in tumor initiation, progression and therapeutic response remain incompletely elucidated. Focusing on the representative subsets of resident T cells, natural killer (NK) cells and macrophages, this review defines the origins of tissue-resident immune cells and elucidates the transcriptional regulatory networks (including TGF-β/IL-33 and RUNX3) that control their differentiation, maintenance, and tissue retention. Meanwhile, we systematically compare tissue-resident immune cells with recruited immune cells and summarize the canonical cell surface markers of resident cells such as CD69 and CD49a. We further reveal the bidirectional plasticity between tissue-resident and recruited immune cells: circulating T cells and monocytes can differentiate into resident subsets under the influence of local cytokine signals such as TGF-β and IFN-γ, while a fraction of tissue-resident immune cells retain the capacity to re-enter the circulation and migrate to distant tissues under inflammatory conditions. On this basis, we dissect the molecular mechanisms underlying the dual pro-tumor and anti-tumor effects exerted by the tissue-resident immune cells in the TME, which are mediated through cytokine regulation, direct contact-mediated cytotoxicity, and indirect modulation of recruited immune cells. Finally, we summarize the multifaceted impacts of conventional cancer therapies (radiotherapy, chemotherapy and targeted therapy) on tissue-resident immune cells, propose innovative therapeutic strategies targeting tissue-resident immune cells, and outline the directions for the development of next-generation molecular targeted anticancer agents. Collectively, this comprehensive review clarifies the mechanistic basis of the dual roles of tissue-resident immune cells in tumor immunity, uncovers their functional plasticity and co-evolutionary mechanisms with the TME, and provides a theoretical framework and novel therapeutic targets for overcoming immune escape in cold tumors.