Cancer therapy resistance converges on immune evasion: a unified framework from immunotherapy to targeted, endocrine, and DNA repair pathways
7 affiliations
- 1Department of Integrated Biomedical and Life Science, Korea University, Seoul, 02841 Republic of Korea
- 2National Research Laboratory for Convergence Degradation Biology, Korea University, Seoul, 02841 Republic of Korea
- 3School of Biosystem and Biomedical Science, College of Health Science, Korea University, Seoul, 02841 Republic of Korea
- 4Division of Medical Oncology, National Cancer Centre Singapore, Singapore, 168583 Singapore
- 5Department of Biochemistry & Molecular Biology, Ajou University School of Medicine, Suwon, 16499 Republic of Korea
- 6BK21 R&E initiative for Advanced Precision Medicine, Department of Biomedical Sciences, Graduate School of Ajou University, Suwon, 16499 Republic of Korea
- 7L-HOPE Program for Community-Based Total Learning Health Systems, Korea University, Seoul, 02841 Republic of Korea
Abstract
Background: Cancer immunotherapy, including immune checkpoint inhibitors, chimeric antigen receptor T-cell (CAR-T) therapy, and bispecific antibodies, has transformed the treatment of advanced malignancies, yet primary and acquired resistance remain major barriers to durable benefit. Across these therapies, resistance reflects the failure of one or more of three shared requirements for effective antitumor immunity: tumor immune visibility, lost through defective antigen presentation and interferon signaling; immune access to tumor nests, restricted by stromal and vascular barriers; and effector cell function, undermined by suppressive myeloid and regulatory populations, metabolic restriction, and loss of tertiary lymphoid structures.
Main body: In this review, we argue that resistance to targeted therapies, endocrine therapies, and PARP inhibitors should not be treated as a problem separate from immunotherapy resistance. Rather, these resistant states often converge on the same three axes that govern immunotherapy resistance (immune visibility, access, and effector function), yielding a unified framework across therapeutic classes. Using canonical immunotherapy resistance as a reference model, we examine how osimertinib resistance, androgen receptor (AR)-pathway-resistant states, and BRCA reversion-mediated PARP inhibitor resistance may remodel these same immune-evasion axes. Targeted therapy resistance provides the most complete case, with epithelial-mesenchymal transition, PD-L1 upregulation, STING suppression, and immune exclusion extending across all three axes. AR pathway reactivation shows plausible links to immune remodeling through direct MHC-I repression and myeloid reprogramming, although the clinical evidence base remains less mature. BRCA reversion illustrates a mechanistically suggestive dual-valence state in which restored DNA repair may diminish innate immune sensing while also generating computationally predicted junctional neopeptides whose immunogenicity remains to be validated.
Conclusions: By reframing resistance as a new immune state that converges on the same three immune-evasion axes rather than a terminal event, this review shifts attention from why a therapy failed to which immune-evasion axis now predominates and how it might be countered. This perspective supports mechanism-matched combination therapy, adaptive molecular monitoring, and cautious exploitation of vulnerabilities generated by the resistant state itself. As an organizing model rather than a claim of uniform causality, the framework now requires prospective validation.
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BibTeX
@article{jeong2026cancer,
title = {{Cancer therapy resistance converges on immune evasion: a unified framework from immunotherapy to targeted, endocrine, and DNA repair pathways}},
author = {Ha-Eun Jeong and Heesun Choi and Wan-Teck Lim and Su Bin Lim and Joon-Yong An},
journal = {Journal of Experimental \& Clinical Cancer Research : CR},
year = {2026},
month = jul,
doi = {10.1186/s13046-026-03798-0},
url = {https://doi.org/10.1186/s13046-026-03798-0},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Cancer therapy resistance converges on immune evasion: a unified framework from immunotherapy to targeted, endocrine, and DNA repair pathways
AU - Ha-Eun Jeong
AU - Heesun Choi
AU - Wan-Teck Lim
AU - Su Bin Lim
AU - Joon-Yong An
PY - 2026
DA - 2026/07/01
JO - Journal of Experimental & Clinical Cancer Research : CR
DO - 10.1186/s13046-026-03798-0
UR - https://doi.org/10.1186/s13046-026-03798-0
AB - Background: Cancer immunotherapy, including immune checkpoint inhibitors, chimeric antigen receptor T-cell (CAR-T) therapy, and bispecific antibodies, has transformed the treatment of advanced malignancies, yet primary and acquired resistance remain major barriers to durable benefit. Across these therapies, resistance reflects the failure of one or more of three shared requirements for effective antitumor immunity: tumor immune visibility, lost through defective antigen presentation and interferon signaling; immune access to tumor nests, restricted by stromal and vascular barriers; and effector cell function, undermined by suppressive myeloid and regulatory populations, metabolic restriction, and loss of tertiary lymphoid structures. Main body: In this review, we argue that resistance to targeted therapies, endocrine therapies, and PARP inhibitors should not be treated as a problem separate from immunotherapy resistance. Rather, these resistant states often converge on the same three axes that govern immunotherapy resistance (immune visibility, access, and effector function), yielding a unified framework across therapeutic classes. Using canonical immunotherapy resistance as a reference model, we examine how osimertinib resistance, androgen receptor (AR)-pathway-resistant states, and BRCA reversion-mediated PARP inhibitor resistance may remodel these same immune-evasion axes. Targeted therapy resistance provides the most complete case, with epithelial-mesenchymal transition, PD-L1 upregulation, STING suppression, and immune exclusion extending across all three axes. AR pathway reactivation shows plausible links to immune remodeling through direct MHC-I repression and myeloid reprogramming, although the clinical evidence base remains less mature. BRCA reversion illustrates a mechanistically suggestive dual-valence state in which restored DNA repair may diminish innate immune sensing while also generating computationally predicted junctional neopeptides whose immunogenicity remains to be validated. Conclusions: By reframing resistance as a new immune state that converges on the same three immune-evasion axes rather than a terminal event, this review shifts attention from why a therapy failed to which immune-evasion axis now predominates and how it might be countered. This perspective supports mechanism-matched combination therapy, adaptive molecular monitoring, and cautious exploitation of vulnerabilities generated by the resistant state itself. As an organizing model rather than a claim of uniform causality, the framework now requires prospective validation.
SN - 0392-9078
SN - 1756-9966
ER -