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

Sep 22, 2026

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Immune checkpoint blockade (ICB) has transformed cancer therapy, but resistance, whether primary or acquired, continues to limit benefit for many patients. Using a large-scale real-world clinicogenomic dataset, the study compares clinical and molecular features across more than 5,000 pan-cancer cases with pre- and post-treatment genomic and transcriptomic data. Acquired resistance after progression shows extended survival alongside a dysfunctional, immune-inflamed tumor microenvironment with persistent inflammatory and interferon programs.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages23

Reading Time58 min

AccessFree to download

Background

Methods

Results

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What is already known on this topic

What this study adds

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Open access To cite: Keddar MR, Carrasco Pro S, Rabbie R, et al. Pancancer analysis in the real-world setting uncovers immunogenomic drivers of acquired resistance postimmunotherapy. Journal for ImmunoTherapy of Cancer 2026;14:e014321 . doi:10 . 1136/ jitc-2025-014321 ► Additional supplemental material is published online only. To view, please visit the journal online ([https://doi.org/10.1136/](https://doi.org/10.1136/)[ ](https://doi.org/10.1136/)[jitc-2025-014321](jitc-2025-014321)) . Accepted 15 April 2026 © Author(s) (or their employer(s)) 2026. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group. For numbered affiliations see end of article. Correspondence to Dr Mohamed Reda Keddar; mohamedreda. keddar@ [astrazeneca.com](astrazeneca.com) Original research Pan-cancer analysis in the real-world setting uncovers immunogenomic drivers of acquired resistance postimmunotherapy Mohamed Reda Keddar ,1 Sebastian Carrasco Pro,2 Roy Rabbie,3 Zeynep Kalender Atak,4 Francesc Muyas,5 Ana Camelo Stewart,1 Scott A Hammond,6 Doug C Palmer,6 Ross Stewart,7 Maureen Carey,8 Kathleen Burke,8 Ben Sidders,9 Jessica Davies,5 Jonathan R Dry ,8 Inigo Martincorena,10 Sajan Khosla,1 Adam Schoenfeld ,11 Martin L Miller12 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 postprogression 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 immunomodulatoryoncogenic 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. INTRODUCTION Immune checkpoint blockade (ICB) has deeply transformed the treatment landscape of cancer, increasingly becoming established asthe standard of care (SoC) across many solid WHAT IS ALREADY KNOWN ON THIS TOPIC | ⇒ Translational studies of acquired immune checkpoint blockade (ICB) resistance focused so far on non-small cell lung cancer or melanoma, highlighting genetic defects in antigen presentation, chronic interferon signaling, or upregulation of alternative immune checkpoints as mechanisms of acquired resistance.
WHAT THIS STUDY ADDS | | --- | | ⇒ We provide the largest and first pan-cancer comparison of acquired versus primary ICB resistance, expanding resistance characterization to understudied indications. We uncover both universal and cancerspecific features of acquired versus primary ICB resistance in the post-progression setting, including extended survival, consistent immune inflammation, and selection

FAQs

What dataset and study design are used to study ICB resistance?

The study leverages a large-scale real-world clinicogenomic dataset and analyzes clinical plus pre- and post-treatment genomic and transcriptomic data across 5,000+ pan-cancer patients.

How does acquired ICB resistance compare with primary resistance clinically?

After post-ICB progression, acquired resistance shows extended survival compared with primary resistance across all cancer types.

What immunogenomic and tumor microenvironment features are linked to acquired resistance?

Acquired resistance is associated with a universally immune-inflamed but dysfunctional tumor microenvironment, including sustained or ICB-induced inflammatory and interferon responses, along with distinct immune-escaped and oncogenic or metabolic alterations.

Sep 22, 2026

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