Accelerating tumor evolution and enhancing immunotherapy efficacy in lung adenocarcinoma based on EXO1 inhibition.

BACKGROUND

Emerging evidence highlights defects in DNA damage repair as critical modulators of tumor immunogenicity, yet the mechanistic interplay between repair pathway dynamics and immune checkpoint inhibitor efficacy remains elusive. This study aims to investigate the role of exonuclease 1 (EXO1), a dual-function nuclease involved in homologous recombination (HR) and mismatch repair (MMR), in immunogenomic regulation and immunotherapy response in lung adenocarcinoma (LUAD).

METHODS

An integrated multi-omics analysis was performed using LUAD cohorts from The Cancer Genome Atlas (TCGA) to assess EXO1 expression, genomic instability, and prognosis. Functional studies were conducted in syngeneic murine models to evaluate the effects of Exo1 ablation on DNA repair pathway kinetics, mutation burden, tumor evolution, and immune cell infiltration. The response to anti-programmed death receptor-1 (PD-1) therapy was assessed in Exo1-deficient versus control tumors.

RESULTS

EXO1 overexpression was strongly associated with genomic instability and poor prognosis in LUAD (hazard ratio =1.047, P =3.72×10-8). In murine models, Exo1 ablation induced a "controlled genomic chaos" state, delaying HR‑mediated fidelity (P<0.0001) while accelerating error‑prone non‑homologous end joining (P<0.01), thereby amplifying clonal mutation burden and tumor evolution. This was accompanied by enrichment of tumor‑specific cytotoxic CD8+ T cells (CD39+ Granzyme B+; P<0.0001). Exo1‑deficient tumors exhibited a 100% objective response to anti‑PD‑1 therapy versus 40% in controls (P<0.001), with a synergistic reduction of tumor mass (77.3% versus 21.2%, P<0.01). Crucially, Exo1 suppression spared MMR functionality while preferentially engaging non‑homologous end joining‑driven immunoediting.

CONCLUSIONS

This work deciphers DNA damage repair‑immune crosstalk governed by biased repair kinetics, and nominates EXO1 abrogation as a transformative strategy to overcome immune checkpoint inhibitor resistance in genomically stable tumors.