Pan-cancer analysis in the real-world setting uncovers immunogenomic drivers of acquired resistance post-immunotherapy

Abstract
Background – Immune checkpoint blockade (ICB) has revolutionized cancer therapy, yet resistance-both primary and acquired-remains a significant obstacle, affecting the majority of patients.

Methods – Here, we leverage a large-scale, real-world clinicogenomic dataset to systematically explore the molecular underpinnings of ICB resistance in the post-progression setting. We analyze over 5,000 pan-cancer patients with clinical and pre-/post-treatment genomic and transcriptomic data and systematically compare the clinical and molecular features of acquired versus primary ICB resistance.

Results – Post-ICB progression, acquired resistance showed extended survival compared to primary resistance across all cancer types. This clinical phenotype was paralleled by a universally immune-inflamed, albeit dysfunctional, tumor microenvironment (TME) at the onset of acquired resistance, with sustained or ICB-induced inflammatory and interferon responses. We confirm previously described mechanisms of acquired resistance, including B2M loss-of-function (LoF) in non-small cell lung cancer (NSCLC), and identify novel potential mediators, including LoF of TGFBR2 in NSCLC, CYLD in head and neck cancer, and RUNX1 in triple-negative breast cancer. Further supporting their involvement in resistance, these acquired ICB alterations associated with immune-escaped TMEs, characterized by active immunomodulatory oncogenic signaling, hyperproliferation and invasiveness, or altered tumor metabolism.

Conclusions – These findings emphasize the heterogeneity of molecular drivers of acquired resistance to ICB within and across cancers, and highlight the potential for personalized therapeutic interventions post-progression to improve patient outcomes.