KIF20A as a driver of anti-PD-1 resistance via PD-L1 downregulation in NSCLC: a biomarker validation and tumor microenvironment analysis.

BACKGROUND: Immune checkpoint inhibitors targeting PD-1 show limited efficacy in non-small cell lung cancer (NSCLC) due to primary resistance. KIF20A, a cell cycle regulator implicated in chemotherapy resistance, may influence tumor immunity, but its role in anti-PD-1 resistance remains unclear.

METHODS: We performed comprehensive bioinformatics analyses to identify KIF20A as a resistance-associated hub gene. Clinical validation was performed in 106 NSCLC patients receiving anti-PD-1 therapy. KIF20A protein expression was assessed by immunohistochemistry (IHC), and tumor microenvironment (TME) profiling was performed using multiplex immunofluorescence (mIHC). Statistical analyses included chi-square tests, Kaplan-Meier survival, Cox regression, and Spearman correlation.

RESULTS: KIF20A was significantly upregulated in NSCLC versus adjacent tissues (63.2% vs. 13.2%, P < 0.001) and associated with lymph node metastasis, poor differentiation, and advanced stage (P < 0.05). High KIF20A expression correlated with primary resistance to PD-1 blockade (P = 0.019) and shorter post-immunotherapy overall survival (HR = 3.40, P = 0.016). Crucially, KIF20A-high tumors exhibited reduced PD-L1⁺ tumor cell density (375.4/mm² vs. 864.8/mm² in KIF20A-low tumors, P = 0.0002), with an inverse correlation (r=-0.249, P = 0.01). Patients with combined KIF20A-high/PD-L1-low expression had the worst prognosis (HR = 6.61, P = 0.030).

CONCLUSIONS: KIF20A drives primary anti-PD-1 resistance in NSCLC through PD-L1 suppression and independently predicts poor survival. The KIF20A/PD-L1 signature stratifies patient risk, positioning KIF20A as both a prognostic biomarker and a therapeutic target to overcome immunotherapy resistance.