The prognostic significance of the IASLC grading system in ALK-positive invasive non-mucinous adenocarcinoma of the lung: correlation with clinicopathological features.

The prognostic value of the International Association for the Study of Lung Cancer (IASLC) grading system in anaplastic lymphoma kinase (ALK)-positive invasive non-mucinous adenocarcinoma (INMA) remains unclear, particularly in relation to the tumor immune microenvironment (TIME). This retrospective study included 108 patients with ALK-positive INMA. Tumors were graded according to the IASLC system. Clinicopathological features, progression-free survival (PFS), and overall survival (OS) were analyzed. Immunohistochemistry was used to assess PD-L1 expression and tumor-infiltrating lymphocytes (TILs), including CD4+, CD8+, and FoxP3+ regulatory T cells. Associations were evaluated using Kaplan-Meier analysis, Cox regression models, and correlation analyses. Higher IASLC grades were significantly associated with more aggressive pathological features, elevated PD-L1 expression, and shorter progression-free survival (PFS). Higher-grade tumors exhibited enhanced T-cell infiltration, predominantly driven by CD8+ T cells, while no significant difference in FoxP3+ Treg density was observed across grades. Notably, the CD4:CD8 ratio decreased, whereas the CD8:FoxP3 ratio increased with tumor grade, indicating a shift toward a CD8-dominant immune microenvironment. Importantly, this cytotoxic predominance occurred in parallel with elevated PD-L1 expression, suggesting an immune context consistent with adaptive immune resistance rather than effective anti-tumor immunity. The IASLC grading system effectively identifies a high-risk subgroup of ALK-positive INMA characterized by aggressive tumor behavior and a dynamically regulated immune microenvironment. High-grade tumors exhibit features of immune engagement coupled with checkpoint-mediated regulation, supporting a model of adaptive immune resistance. These findings underscore the necessity of combination therapeutic strategies that simultaneously target ALK and immune checkpoint modulation in high-grade INMA.