Role of circRNA in modulating tumor microenvironment: From mycobacterial infection to lung cancer.

e20025 Background: Tuberculosis (TB) is significantly associated with an increased risk of lung cancer, yet the underlying immune mechanisms remain incompletely defined. TB infection alters the lung microenvironment and profoundly affects macrophages, which are key regulators of the tumor microenvironment. PD-L1 expression is upregulated in TB and can influence macrophage polarization. Circular RNAs (circRNAs) are emerging as important regulators of immune checkpoints such as PD-L1. This study investigates whether TB-induced circRNAs regulate PD-L1 expression and macrophage polarization, particularly under cancer-cell-associated conditions that enhance the formation of a tumor-permissive microenvironment. Methods: Patients with newly diagnosed lung cancer or active TB were prospectively enrolled at Taipei Veterans General Hospital. Peripheral blood mononuclear cells (PBMCs) were collected to analyze circRNA and PD-L1 expression by RT-qPCR. In vitro, THP-1 monocytes were differentiated into M0, M1, and M2 macrophages. Macrophages were stimulated with TB lysate or ESAT-6 to model TB-induced changes. A549 lung cancer cells were co-cultured with macrophages in a transwell system to assess tumor–macrophage crosstalk. siRNA knockdown was used to evaluate the effect of specific circRNAs on PD-L1 expression. Macrophage polarization and cytokine profiles were analyzed by RT-qPCR. Results: TB stimulation increased PD-L1 expression and favored an M2-skewed macrophage phenotype. In co-culture, M2 macrophages promoted A549 cell survival and further upregulated PD-L1, whereas M1 macrophages did not. A specific circRNA (hsa_circ_0000190) was differentially expressed in TB and lung cancer patients and showed dynamic, polarization-dependent changes. ESAT-6 stimulated macrophages co-cultured with A549 cells exhibited enhanced M2 polarization and elevated circRNA expression. Knockdown of this circRNA significantly reduced PD-L1 expression, confirming its regulatory role. Conclusions: These findings support a model in which TB infection remodels the lung microenvironment via circRNA-dependent PD-L1 upregulation and macrophage reprogramming toward an M2 phenotype. The identified circRNA–PD-L1–macrophage polarization axis provides a plausible mechanistic link between TB and increased lung cancer risk and suggests a potential target for early intervention and risk stratification in TB-affected populations.