Dynamic Interplay Between Tumor Cells and the Immune System

Tumorigenesis begins with the malignant transformation of a normal cell and evolves through reiterative cycles of clonal expansion, genetic diversification, and clonal selection of transformed cells (1).In parallel with these tumor cell-intrinsic evolutionary processes, tumors progressively remodel their surrounding tissue architecture, giving rise to a complex tumor-associated stroma composed of diverse stromal and immune cell populations, extracellular matrix components, and soluble mediators.The stroma provides both structural and functional framework that supports parenchymal cells, the primary functional cells of tissues.As parenchymal cells undergo malignant transformation during carcinogenesis, the stroma becomes progressively enriched with diverse stromal cell populations and extracellular matrix components.The dynamic and reciprocal interactions between cancer cells and stromal components collectively establish the tumor microenvironment (TME), which can either promote or constrain the tumor growth depending on the context.The immune system eliminates cancer cells that express neoantigens or stress-induced molecules.However, immune pressure also shapes tumor evolution by selecting for variants that evade immune-mediated destruction, which drives immunoediting of cancer cells (2).The immune-escaping subclones eventually dominate advanced tumors, frequently accompanied by profound remodeling of the TME.Although antitumor immune cells may infiltrate the cancer parenchyma or remain localized within the stroma, many effector immune cell populations become functionally exhausted and lose their cytotoxic capacity.Chronic Ag exposure and persistent inhibitory receptor signaling drive immune exhaustion.Metabolic stress and a suppressive TME further limit durable tumor control.Consequently, a major goal of contemporary cancer immunology research is to elucidate the mechanisms underlying immune failure and to devise strategies that restore or redirect effective antitumor immunity.This special issue of Immune Network brings together a collection of review articles that address key issues regarding TME, tumor-intrinsic programs, immune cell heterogeneity and exhaustion, systemic regulation, and emerging immunotherapeutic strategies.First, a tumor cell-centric framework for immune refractoriness was addressed, arguing that durable resistance to immunotherapy is rooted not only in immune cell dysfunction but also in intrinsic oncogenic and epigenetic programs within tumor cells themselves (3).These programs actively shape the TME by suppressing Ag presentation, promoting aberrant