Spatial single-cell proteotyping reveals immunotherapy-resistant features within the complex tumor microenvironment of metastatic NSCLC.
[BACKGROUND] Immune checkpoint inhibitors (ICIs) targeting the programmed cell death-1 axis have revolutionized metastatic non-small cell lung cancer (mNSCLC) treatment.
APA
Isomoto K, Haratani K, et al. (2026). Spatial single-cell proteotyping reveals immunotherapy-resistant features within the complex tumor microenvironment of metastatic NSCLC.. The Journal of clinical investigation. https://doi.org/10.1172/JCI195021
MLA
Isomoto K, et al.. "Spatial single-cell proteotyping reveals immunotherapy-resistant features within the complex tumor microenvironment of metastatic NSCLC.." The Journal of clinical investigation, 2026.
PMID
41805727
Abstract
[BACKGROUND] Immune checkpoint inhibitors (ICIs) targeting the programmed cell death-1 axis have revolutionized metastatic non-small cell lung cancer (mNSCLC) treatment. However, disease progression remains a concern, and the role of the complex tumor microenvironment (TME) in treatment failure is not fully understood.
[METHODS] In this biomarker study involving 103 patients with mNSCLC-including 81 patients who received ICI treatment-we evaluated the association between heterogeneous immune cell subsets and ICI efficacy through single-cell spatial profiling of pretreatment tumor tissue, using a 29-marker multiplex immunohistochemistry platform built for in-depth dissection of the TME.
[RESULTS] Among various types of intratumoral lymphocytes including T-helper 1 cells, regulatory T cells, and natural killer cells, only CD8+ T cells (TILs) were associated with ICI efficacy. Computational tissue segmentation underscored the importance of direct physical interactions between CD8+ TILs and cancer cells for ICI efficacy. TIL phenotyping identified CD39/CD103/Ki-67 positivity as a hallmark of exhausted yet functional tumor-reactive CD8+ TILs. Immunosuppressive tumor-associated macrophages (TAMs) and cancer-associated fibroblasts were independent unfavorable adversaries. High CD73 expression on cancer cells was suggested to confer tolerance to ICI in EGFR/ALK-oncogene+ NSCLC, potentially through M2-TAM accumulation and aberrant angiogenesis.
[CONCLUSION] Our study delineates the clinical relevance of heterogeneous immune cell subsets in ICI-treated mNSCLC, aiding the development of targeted therapeutic strategies.
[TRIAL REGISTRATION] Not applicable because this is a retrospective study.
[FUNDING] Osaka Cancer Society, KANAE Foundation for the Promotion of Medical Science, SGH Foundation, and YOKOYAMA Foundation for Clinical Pharmacology.
[METHODS] In this biomarker study involving 103 patients with mNSCLC-including 81 patients who received ICI treatment-we evaluated the association between heterogeneous immune cell subsets and ICI efficacy through single-cell spatial profiling of pretreatment tumor tissue, using a 29-marker multiplex immunohistochemistry platform built for in-depth dissection of the TME.
[RESULTS] Among various types of intratumoral lymphocytes including T-helper 1 cells, regulatory T cells, and natural killer cells, only CD8+ T cells (TILs) were associated with ICI efficacy. Computational tissue segmentation underscored the importance of direct physical interactions between CD8+ TILs and cancer cells for ICI efficacy. TIL phenotyping identified CD39/CD103/Ki-67 positivity as a hallmark of exhausted yet functional tumor-reactive CD8+ TILs. Immunosuppressive tumor-associated macrophages (TAMs) and cancer-associated fibroblasts were independent unfavorable adversaries. High CD73 expression on cancer cells was suggested to confer tolerance to ICI in EGFR/ALK-oncogene+ NSCLC, potentially through M2-TAM accumulation and aberrant angiogenesis.
[CONCLUSION] Our study delineates the clinical relevance of heterogeneous immune cell subsets in ICI-treated mNSCLC, aiding the development of targeted therapeutic strategies.
[TRIAL REGISTRATION] Not applicable because this is a retrospective study.
[FUNDING] Osaka Cancer Society, KANAE Foundation for the Promotion of Medical Science, SGH Foundation, and YOKOYAMA Foundation for Clinical Pharmacology.