Phd in NETWORK ONCOLOGY AND PRECISION MEDICINE

Thesis title: Genetic and transcriptional hallmarks of resistance to immunotherapy in NSCLC

The accumulation of somatic mutations is a hallmark of tissue ageing and cancer development. Somatic mutagenesis occurs throughout life, progressively reshaping the genomic landscape of healthy tissues. Clonal expansion of cells carrying driver mutations leads to functional decline through positive selection favoring proliferation over differentiation in stem cell populations. These evolutionary dynamics underpin both ageing and cancer: mechanisms that suppress tumorigenesis may promote ageing by limiting tissue regeneration, while their loss can enable malignant transformation. In lung cancer, one of the most lethal malignancies worldwide, tumor evolution unfolds under constant selective pressure from the immune system. Immune surveillance shapes the evolutionary trajectory of lung cancer long before therapeutic intervention, influencing both tumor progression and immune escape. The introduction of immune checkpoint inhibitors targeting PD-(L)1 and CTLA-4 has transformed the treatment of non–small cell lung cancer (NSCLC), achieving durable responses and redefining expectations for long-term survival. Within this context, NRF2 pathway activation has emerged as a key determinant of immune resistance. Our work identifies KEAPness, a transcriptional phenotype reflecting NRF2 activation in the absence of KEAP1 or NFE2L2 mutations. KEAPness recapitulates the biological and clinical effects of genetic NRF2 activation, including immune exclusion, transcriptional stability, and resistance to immune checkpoint blockade. Its presence across multiple tumor types—particularly squamous carcinomas—suggests that non-genetic NRF2 activation represents a conserved adaptive mechanism in cancer. NRF2-driven metabolic and immunologic remodeling therefore represents a potential therapeutic vulnerability and a rationale for developing strategies to overcome resistance to immunotherapy.