Leveraging mitochondrial-programmed cell death dynamics to enhance prognostic accuracy and immunotherapy efficacy in lung adenocarcinoma

Abstract

Background Lung adenocarcinoma (LUAD) is a highly heterogeneous disease, posing significant challenges to accurate prognosis prediction. Mitochondria play a central role in the energy metabolism of eukaryotic cells and can influence programmed cell death (PCD) mechanisms, which are critical in tumorigenesis and cancer progression. However, the prognostic significance of the interplay between mitochondrial function and PCD in LUAD requires further investigation.Methods We analyzed data from 1231 LUAD patients across seven global cohorts to develop a mitochondrial-related PCD signature (MPCDS) using machine learning. Validation was done using six immunotherapy cohorts (LUAD, melanoma, clear cell renal cell carcinoma; n=935) and a pan-cancer cohort of 21 tumor types. An in-house LUAD tissue cohort (n=100) confirmed the prognostic significance of nucleoside diphosphate kinase 4 (NME4). In vivo and in vitro experiments explored NME4’s role in immune exclusion.Results The MPCDS demonstrated strong predictive performance for prognosis in LUAD patients, surpassing 114 previously published LUAD signatures. Additionally, MPCDS effectively predicted outcomes in immunotherapy patients (including those with LUAD, melanoma, and clear cell renal cell carcinoma). Biologically, MPCDS was significantly associated with immune features, with the high MPCDS group exhibiting reduced immune activity and a tendency towards cold tumors. NME4, a key gene within the MPCDS (correlation=0.55, p<0.05), was associated with poorer prognosis in LUAD patients with high expression, particularly in CD8 desert phenotypes, as validated by our in-house cohort. Multiplex immunofluorescence confirmed the spatial colocalization and exclusion relationship between NME4 and immune cells such as CD3+ T cells and CD20+ B cells. Further experiments revealed that NME4 regulated the proliferation and invasion of LUAD cells both in vitro and in vivo. Importantly, inhibiting NME4 increased the abundance and activity of CD8+ T cells and enhanced the antitumor immunity of anti-programmed cell death protein-1 therapy in vivo.Conclusion The MPCDS provides personalized risk assessment and immunotherapy interventions for individual LUAD patients. NME4, a key gene within the MPCDS, has been identified as a novel oncogene associated with immune exclusion and may serve as a new target for LUAD intervention and immunotherapy.