Vγ1 γδ T cells steer airway macrophages toward a profibrotic response in an autochthonous lung cancer mouse model

γδ T cells are important for host defense at the respiratory mucosa, acting directly or through interactions with other cells. However, how γδ T cells influence other immune cells in the lung remains unclear. Using a genetically engineered mouse model of lung cancer, we show that tumors drive expansion of both CD27⁺ and CD27^- γδ T cells. Advanced microscopy techniques indicated that CD27^- γδ T cells are enriched in tumors, whereas CD27⁺ γδ T cells are more prone to interact with macrophages in tumor-associated adventitial cuffs. SiglecF^low profibrotic airway macrophages were more prevalent in lung tumor-bearing mice than tumor-free mice. This profibrotic subset was reduced in lungs when the cancer model was crossed to Tcrd knockout mice or treated with Vγ1-depleting antibodies but not in TcrgV4/6 knockout mice. Thus, our findings implicate Vγ1 γδ T cells in driving tumor-associated airway macrophage functional imprinting. Determining the translatability to human health may offer new avenues for refining patient management and immunotherapeutic strategies.