Peripheral TERT- positive leukocytes as a biomarker of the local and systemic immune failure in early-stage lung adenocarcinoma progression

The prognosis of early-stage lung adenocarcinoma (LUAD) worsens significantly during the progression from adenocarcinoma in situ/minimally invasive adenocarcinoma (AIS/MIA) to invasive adenocarcinoma (IAC), emphasizing the importance of understanding the molecular mechanisms underlying this transition for effective clinical intervention. This study analyzed data from 990 eligible early-stage LUAD patients meeting the following inclusion criteria: written informed consent, absence of neoadjuvant therapy, planned surgical resection, postoperative pathological confirmation of LUAD, and an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1. Analysis of a retrospective cohort of 601 stage I LUAD patients demonstrated a significant correlation between the extent of tumor invasion and 5-year survival rates. Transcriptomic profiling revealed a progressively immunosuppressive tumor microenvironment (TME) during the AIS/MIA-to-IAC transition, characterized by dysfunctional immune cells and diminished local anti-tumor immunity. Notably, peripheral blood analysis from 389 patients showed a significant decrease in telomerase reverse transcriptase-positive (TERT +) leukocytes with tumor progression, a change detectable earlier than circulating tumor cells (CTCs). Two-year follow-up data corroborated these findings. This study elucidates key biological events in early-stage LUAD progression, revealing that the tumor remodels both local and systemic immunity to facilitate its advancement. The reduction in peripheral TERT + leukocytes emerges as a potential non-invasive biomarker for the early detection of malignant progression, supporting the rationale for immune-based interventions at earlier disease stages.