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Radiomics and Machine Learning in Medical Imaging / Ferroptosis and Cancer Prognosis · Journal article
Frontiers in Immunology · August 11, 2026
Encouraging direction, but not yet definitive.
This retrospective multi-cohort study proposes intratumoral heterogeneity (measured by Shannon entropy) as a biomarker associated with better immunotherapy outcomes and lower recurrence risk in NSCLC. Low intratumoral heterogeneity (ITH-L) correlated with higher response rates and longer survival in advanced disease, and with improved recurrence-free survival in early-stage surgical patients, but the evidence remains observational without prospective validation.
Retrospective cohort analysis with multi-cohort validation. Advanced NSCLC patients receiving immunotherapy in POPLAR, OAK, and Hellmann2018 cohorts; early-stage surgical NSCLC patients with radical treatment from in-house cohort. Specific eligibility criteria not detailed in abstract.. Intervention: Intratumoral heterogeneity measurement by Shannon entropy; TMB and circulating tumor DNA assessed as combination biomarkers.. Compared with: Low intratumoral heterogeneity (ITH-L) versus high intratumoral heterogeneity (ITH-H) groups; TMB-stratified subgroups.. n = 625.
In Hellmann2018 cohort, ITH-L correlated with higher DCB rate, ORR, and longer mPFS compared to high ITH ITH-L/TMB-H combined phenotype showed significantly better DCB, ORR, and mPFS than other combinations POPLAR/OAK validation confirmed ITH-L association with higher DCB, ORR, longer mPFS, and longer mOS
Safety was not reported in the material analysed. Check the source before drawing any conclusion about harm.
If validated prospectively, ITH measurement could become a routine biomarker for predicting immunotherapy response and recurrence risk in NSCLC, potentially informing treatment selection and surveillance strategies. Current evidence supports further investigation but is not yet ready to guide clinical practice.
Retrospective analysis across multiple cohorts showing associations between intratumoral heterogeneity and immunotherapy response and recurrence, but limited by observational design, lack of prospective validation, and surrogate endpoints rather than hard clinical outcomes.
As stated by the source record.
Quoted from the source exactly as published.
If validated prospectively, ITH measurement could become a routine biomarker for predicting immunotherapy response and recurrence risk in NSCLC, potentially informing treatment selection and surveillance strategies. Current evidence supports further investigation but is not yet ready to guide clinical practice.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
Background Intratumoral heterogeneity (ITH) is associated with poor prognosis in various solid tumors. However, its use as a predictive biomarker for immunotherapy in advanced non-small cell lung cancer (NSCLC) is still lacking. Methods We used Maftools to analyze somatic variants of NSCLC from independent cohorts (POPLAR, OAK, Hellmann2018) including 504 patients with advanced NSCLC. Additionally, 121 patients (in-house cohort) with NSCLC who received radical treatment and underwent 733-panel NGS testing of surgical samples were included. We used Shannon entropy to measure ITH, analyzed correlation with immunogenic markers, and explored ITH’s prognostic effect on immunotherapy and its role in predicting postoperative recurrence risk. Using the TCGA cohort, we compared genetic characteristics between low ITH (ITH-L) and high ITH (ITH-H) groups, assessed mutational profiles, and evaluated associations between ITH scores and immune cell populations. Results In the Hellmann2018 cohort, ITH-L correlated with higher durable clinical benefit (DCB) rate, objective response rate (ORR), and median progression-free survival (mPFS), highlighting ITH-L as a potential positive predictor for ICI therapy. Combining ITH with TMB revealed that ITH-L/TMB-H patients had significantly better DCB, ORR, and mPFS, supporting the potential predictive value of ITH when evaluated together with TMB. Validation in POPLAR/OAK cohorts supported the association of ITH, alone or combined with TMB, with immunotherapy outcomes. ITH-L patients exhibited higher DCB, ORR, longer mPFS, and median overall survival (mOS). Combining ITH and circulating tumor DNA validated these findings. In early-stage surgical NSCLC patients, ITH-L was associated with significantly higher median recurrence-free survival (mRFS). Mechanistically, the ITH-L group showed elevated TMB, neoantigen (SNV), and subclonal genome fraction, alongside reduced HRD scores and CNV burden. Mutational analysis identified XIRP2 as the most frequently altered gene, enriched in the ITH-L group, while SHOX2 was the only gene with higher frequency in the ITH-H group. Immune infiltration analysis revealed significant differences in M1 macrophages, activated memory CD4+ T cells, and naive CD4+ T cells between groups. Conclusions ITH may serve as a potential biomarker associated with immunotherapy outcomes in advanced NSCLC and postoperative recurrence risk in early-stage surgical patients.
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