MFF Promotes Aggressive Phenotypes and Immunosuppression in Lung Adenocarcinoma via Mitochondrial Dysregulation

Lung Adenocarcinoma (LUAD) remains a leading cause of cancer mortality, driving the need for novel prognostic markers and therapeutic targets. Mitochondrial dynamics, particularly fission, have emerged as a crucial regulator of tumor progression. Emerging evidence highlights the interplay between mitochondrial proteins and immune modulation, yet the role of Mitochondrial Fission Factor (MFF) in shaping the tumor immune microenvironment, particularly its involvement in non-canonical immune checkpoints, remains largely unexplored in LUAD. Herein, we investigate the expression and clinical significance of MFF in LUAD, and explore its potential associations with mitochondrial dynamics, metabolic reprogramming, and immune modulation.

Gene expression and clinical data were obtained from The Cancer Genome Atlas (TCGA) LUAD cohort for bioinformatics analysis. Validation at the protein level was performed using Immunohistochemistry (IHC) on a Tissue Microarray (TMA) containing 42 evaluable paired LUAD and adjacent normal tissues. Bioinformatics analyses included differential expression, survival (Kaplan-Meier, Cox regression), Protein-Protein Interaction (PPI) networks, Gene Set Enrichment Analysis (GSEA), and immune infiltration profiling.

MFF was significantly overexpressed in LUAD at both transcript and protein levels and correlated with advanced disease stages, male gender, and poor survival. It served as a robust prognostic biomarker even in early-stage and node-negative subgroups. Beyond its expected association with mitochondrial dynamics regulators (DNM1L/DRP1, MFN1), MFF expression strongly correlated with a hyperactive OXPHOS transcriptional program, identifying a distinct metabolic phenotype. MFF high tumors were characterized by a distinctive immune checkpoint landscape, with reduced expression of PD-1 and CTLA-4, but marked upregulation of B7-H3 (CD276), coupled with broad suppression of immune infiltration and the antigen presentation machinery.

Our findings establish MFF as a multifunctional hub linking mitochondrial plasticity to metabolic adaptation and immune evasion in LUAD. The strong OXPHOS association suggests MFF-high tumors may act as metabolic sinks, creating a nutrient-deprived microenvironment hostile to infiltrating immune cells. The distinct B7-H3-dominant checkpoint profile further defines a non-inflamed "immune desert" phenotype, offering a potential explanation for resistance to conventional PD-1/CTLA-4 blockade. While our data do not establish causation, we propose three testable hypotheses for this immunosuppressive phenotype: metabolic competition, shared upstream regulation (e.g., androgen receptor signaling), and stress-induced checkpoint switching.

MFF drives LUAD progression by orchestrating mitochondrial plasticity and fostering a metabolically distinct, B7-H3-dominant "cold" tumor microenvironment. This positions MFF as a robust prognostic biomarker and identifies MFF-high patients as a specific subgroup that may resist conventional immunotherapy but could benefit from emerging B7-H3-directed therapies, including antibody-drug conjugates or chimeric antigen receptor (CAR)-T cells. Further functional studies are warranted to distinguish whether MFF actively regulates these processes or serves as a marker of this aggressive tumor niche.