Immune checkpoint blockade (ICB) has limited efficacy in microsatellite stable (MSS) colorectal cancer (CRC) due to an immunosuppressive tumour microenvironment. Although loss of phosphatase and tensin homologue (PTEN) occurs in 19–36% of MSS CRC cases, its specific role in driving immune exclusion and ICB resistance remains elusive.
To investigate whether PTEN deficiency promotes resistance to ICB in MSS CRC.
An integrative analysis of clinical cohort and The Cancer Genome Atlas (TCGA) database was performed to establish the correlation between PTEN expression and therapeutic response. Single-cell RNA sequencing and flow cytometry were used to identify changes in the tumour immune microenvironment. Immunohistochemistry, mass spectrometry, co-immunoprecipitation and confocal microscopy were employed to dissect the non-canonical function of PTEN.
PTEN low expression was strongly associated with reduced CD8+ T-cell infiltration and poor survival in patients receiving ICB. Mechanistically, we identified a non-canonical function of PTEN that physically interacts with and stabilises KEAP1 via the C2 domain, shielding KEAP1 from p62-mediated degradation. Consequently, PTEN deficiency promoted KEAP1 degradation and subsequent NRF2 hyperactivation, which transcriptionally upregulated selective-autophagy machinery, thereby driving the selective lysosomal degradation of major histocompatibility complex (MHC)-I. This process abolished CD8+ T-cell recognition and effector functions, resulting in immune evasion. Crucially, pharmacological inhibition of NRF2 with ML385 restored cell surface MHC-I levels and sensitised PTEN-deficient tumours to anti-programmed cell death protein 1 therapy.
PTEN deficiency promotes immune evasion in MSS CRC via an NRF2-dependent axis that triggers autophagy-mediated degradation of MHC-I. Targeting NRF2 represents a promising strategy to enhance the efficacy of immunotherapy in PTEN-deficient MSS CRC.
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