Front Immunol. 2026 May 8;17:1780459. doi: 10.3389/fimmu.2026.1780459. eCollection 2026.

ABSTRACT

Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and its ligand programmed death-ligand 1 (PD-L1) have transformed the management of advanced lung cancer, yet most patients experience primary resistance, hyperprogressive disease (HPD), or clinically significant immune-related adverse events (irAEs). Multi-omics technologies now enable integrated interrogation of tumor, microenvironmental, host, and clinical determinants of these divergent outcomes. In this review, we first discuss the biological and clinical foundations of PD-1/PD-L1 blockade in non-small cell and small cell lung cancer, and summarize the spectrum of resistance, HPD, and irAEs observed in trials and real-world practice. We then describe multi-omics study frameworks that connect genomics, transcriptomics, epigenomics, proteomics, metabolomics, radiomics, and microbiome profiling with these outcome phenotypes. Building on this foundation, we synthesize evidence for composite biomarkers of primary and acquired resistance, delineate emerging multi-omics signatures of HPD, and examine host- and tumor-derived multi-omics correlates of organ-specific and systemic irAEs. We further propose an efficacy-risk quadrant framework to guide clinical decision-making when favorable efficacy predictors coexist with elevated risk of severe adverse outcomes, and outline a three-step approach for high-efficacy/high-risk patients: joint probability reporting, multi-omics guided mitigation, and dynamic reassessment. Finally, we evaluate translational strategies that integrate multi-omics scores into baseline risk stratification, dynamic monitoring with attention to technical challenges such as distinguishing true progression from ctDNA pseudoprogression, and biomarker-driven trial design, while assessing the evidence level and translational readiness of candidate assays from retrospective discovery to clinical implementation. A clinical case illustrates how multi-omics can link baseline risk stratification, regimen selection, and longitudinal monitoring into a coherent action plan, while acknowledging that artificial intelligence-driven models remain investigational and real-world application still relies on clinician judgment. Collectively, this review defines how integrated multi-omics biomarkers can be leveraged to predict resistance, HPD, and immune-related toxicity, and to refine patient selection and management during PD-1/PD-L1 therapy in lung cancer.

PMID:42183274 | PMC:PMC13194140 | DOI:10.3389/fimmu.2026.1780459

Front Immunol. 2026 May 8;17:1780459. doi: 10.3389/fimmu.2026.1780459. eCollection 2026.

ABSTRACT

Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and its ligand programmed death-ligand 1 (PD-L1) have transformed the management of advanced lung cancer, yet most patients experience primary resistance, hyperprogressive disease (HPD), or clinically significant immune-related adverse events (irAEs). Multi-omics technologies now enable integrated interrogation of tumor, microenvironmental, host, and clinical determinants of these divergent outcomes. In this review, we first discuss the biological and clinical foundations of PD-1/PD-L1 blockade in non-small cell and small cell lung cancer, and summarize the spectrum of resistance, HPD, and irAEs observed in trials and real-world practice. We then describe multi-omics study frameworks that connect genomics, transcriptomics, epigenomics, proteomics, metabolomics, radiomics, and microbiome profiling with these outcome phenotypes. Building on this foundation, we synthesize evidence for composite biomarkers of primary and acquired resistance, delineate emerging multi-omics signatures of HPD, and examine host- and tumor-derived multi-omics correlates of organ-specific and systemic irAEs. We further propose an efficacy-risk quadrant framework to guide clinical decision-making when favorable efficacy predictors coexist with elevated risk of severe adverse outcomes, and outline a three-step approach for high-efficacy/high-risk patients: joint probability reporting, multi-omics guided mitigation, and dynamic reassessment. Finally, we evaluate translational strategies that integrate multi-omics scores into baseline risk stratification, dynamic monitoring with attention to technical challenges such as distinguishing true progression from ctDNA pseudoprogression, and biomarker-driven trial design, while assessing the evidence level and translational readiness of candidate assays from retrospective discovery to clinical implementation. A clinical case illustrates how multi-omics can link baseline risk stratification, regimen selection, and longitudinal monitoring into a coherent action plan, while acknowledging that artificial intelligence-driven models remain investigational and real-world application still relies on clinician judgment. Collectively, this review defines how integrated multi-omics biomarkers can be leveraged to predict resistance, HPD, and immune-related toxicity, and to refine patient selection and management during PD-1/PD-L1 therapy in lung cancer.

PMID:42183274 | PMC:PMC13194140 | DOI:10.3389/fimmu.2026.1780459

Clin Cancer Res. 2026 Mar 18. doi: 10.1158/1078-0432.CCR-25-4153. Online ahead of print.

ABSTRACT

PURPOSE: Intestinal low-dose irradiation (ILDR) may enhance immunotherapy efficacy by modulating the gut microbiota and metabolism; however, its role in metastatic non-small cell lung cancer (mNSCLC), particularly in the first-line setting, remains unclear.

EXPERIMENTAL DESIGN: This multicenter retrospective and prospective study included mNSCLC patients receiving first- and second-line programmed cell death protein 1 (PD-1) inhibitors along with abdominopelvic radiotherapy between 2018 and 2025. Patients were stratified by the mean intestinal radiation dose into <1 Gy, 1-3 Gy, and >3 Gy groups and treatment outcomes were compared. The blood and fecal samples were subjected to multi-omics profiling.

RESULTS: g>309 patients were included in the retrospective analysis. Optimal efficacy was observed with a small intestinal mean radiation dose (SIMRD) of 1-3 Gy, showing longer progression-free survival (PFS, 10.2 months) and overall survival (OS, 22.8 months) (P < 0.01), which was consistent across subgroups. Compared with 1-3 Gy, SIMRD >3 Gy (Hazard ratio [HR] = 4.87, P < 0.001) and <1 Gy (HR = 1.85, P < 0.001) independently predicted worse OS. Prospective results confirmed the best disease control rate (P = 0.041) and PFS (P = 0.046) with SIMRD of 1-3 Gy. Responders were enriched in Bacillota, Clostridia, and indole derivatives, particularly indole-3-carboxylic acid. Moreover, the 1-3 Gy group exhibited increased circulating macrophage inflammatory protein-3α and reduced circulating α4β7+ regulatory T cells.

CONCLUSIONS: ILDR influences the efficacy of PD-1 blockade in patients with mNSCLC, particularly when SIMRD is maintained within the 1-3 Gy range, likely through modulation of the gut microbiota-metabolite-immune axis.

PMID:41849236 | DOI:10.1158/1078-0432.CCR-25-4153