Immune regulatory mechanisms in the tumor microenvironment and their applications in cancer therapy: from basic research to clinical translation.

Cancer immunotherapy has significantly advanced oncological care, offering durable responses for a subset of patients. However, the efficacy of these treatments is frequently hindered by primary and acquired resistance orchestrated by the tumor microenvironment (TME). Within the highly heterogeneous TME, multidirectional interactions between tumor cells, stromal components, and infiltrating immune cells actively suppress anti-tumor immunity. This review comprehensively examines the multifaceted immune regulatory mechanisms within the TME, with a specific focus on the immunosuppressive roles of tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs). We further explore how metabolic reprogramming-such as the Warburg effect, lactate accumulation, and hypoxia-creates a hostile niche that impairs effector T cell function and promotes immune evasion. Bridging basic research to clinical translation, we systematically evaluate current TME-targeted therapeutic strategies, including immune checkpoint inhibitors (ICIs), adoptive cell therapies, oncolytic viruses, and anti-angiogenic agents. The review also highlights emerging combinatorial approaches designed to remodel the immunosuppressive stroma and normalize the tumor vasculature. Finally, we discuss critical challenges in clinical application, such as tumor heterogeneity and the need for predictive biomarkers, emphasizing that personalized strategies tailored to specific TME phenotypes are essential for overcoming therapeutic resistance and improving patient outcomes.