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Review Open Access

Post‑translational modification‑governed immune states in cancer immunity: Biomarker implications for checkpoint competence, tumor visibility and immunotherapy resistance (Review)

  • Authors:
    • Jinghao Pan
    • Boyang Li
    • Ruonan Lin
    • Chenlu Fang
    • Lucy Yue Lau
    • Zehao Hong
    • Yi Chen
  • View Affiliations / Copyright

    Affiliations: Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China, Department of Public Health, Harvard Medical School, Boston, MA 02115, USA, Cancer Research Institute, The Affiliated Cancer Hospital of Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region 830011, P.R. China
    Copyright: © Pan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 119
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    Published online on: August 21, 2026
       https://doi.org/10.3892/ijo.2026.5932
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Abstract

Immune escape and therapeutic resistance remain major obstacles to durable benefit from cancer immunotherapy, yet transcript‑based or abundance‑based biomarkers often fail to capture the regulatory states that determine effective immune control. Post‑translational modifications (PTMs) form a dynamic protein‑state layer that rapidly reshapes protein stability, trafficking, complex assembly, and signaling persistence under tumor‑intrinsic and therapy‑imposed stress. In the present review, a biomarker‑oriented framework is proposed in which PTM biology is interpreted through three recurrent immune constraints: Checkpoint competence, tumor visibility and stress‑conditioned immune‑state programming. Within this framework, programmed death‑ligand 1 is viewed as a protein‑state biomarker problem rather than a static expression marker; tumor visibility is defined by durable antigen‑presentation competence and interferon‑linked reinforcement; and stress‑driven immune dysfunction is interpreted through metabolite‑sensitive PTM rewiring and chromatin‑coupled suppressive stabilization. Rather than cataloguing PTMs comprehensively in cancer immunity, the present review focuses on five core exemplar PTM axes, glycosylation, palmitoylation, ubiquitin editing, phosphorylation and lactylation, because they repeatedly map to rate‑limiting immune constraints, are supported by mechanistic evidence, and represent candidate assay‑compatible or intervention‑relevant state variables at differing levels of translational maturity. It is further outlined how integrated proteogenomic, immuno‑peptidomic, and spatial datasets can be used to discover candidate PTM‑state biomarkers, validate mechanism‑proximal readouts in prespecified pretreatment and on‑treatment settings, and prioritize single or co‑dominant state constraints for patient stratification, pharmacodynamic monitoring, and rational combination design. By organizing PTM biology around measurable state variables rather than modification class alone, the present review provides a phase‑aware translational framework for candidate biomarker discovery, fit‑for‑purpose validation, constraint‑guided stratification, and therapeutic prioritization in cancer immunotherapy.
View Figures

Figure 1

Selected milestones in PTM-centric
cancer-immune-resistance research. This timeline highlights
representative landmark advances linking PTMs to tumor
antigenicity, checkpoint-state control, immune evasion and
immunotherapy resistance, with particular emphasis on
glycosylation, ubiquitination, palmitoylation, phosphorylation and
lactylation. Together, these developments illustrate how PTMs
progressively emerged as mechanistically and translationally
relevant determinants of cancer immune resistance. PTM,
post-translational modification; PD-1, programmed cell death
protein 1; PD-L1, programmed death-ligand 1.

Figure 2

PTM-defined control of the
synapse-competent PD-L1 pool. PD-L1 checkpoint output is governed
by a functionally relevant surface pool at the tumor-immune
interface rather than by total abundance alone. Glycosylation,
palmitoylation and ubiquitin editing converge to shape this pool by
regulating epitope accessibility and assay alignment, membrane
persistence, and rescue from turnover, respectively. These state
variables determine sustained PD-1 inhibitory signaling and provide
a translational framework for function-matched readouts,
intervention design, and patient stratification. PTM,
post-translational modification; PD-L1, programmed death-ligand 1;
DUB, deubiquitinase; IHC, immunohistochemistry.

Figure 3

A two-layer PTM-controlled
architecture of tumor visibility: Antigen presentation and
IFNγ-STAT1 reinforcement. Tumor visibility is determined by two
coupled layers: The antigen-presentation machinery that governs
peptide loading, trafficking, and surface pMHC display, and the
IFNγ-STAT1 reinforcement layer that sustains IFNγR-JAK1 complex
stability, signaling amplitude, signal duration, and nuclear
maintenance of visibility programs. PTM-dependent disruption at
either layer can weaken durable tumor visibility, reduce effective
immune priming and reinforcement, and contribute to primary
nonresponse. Direct readout opportunities include pMHC display,
HLA-I immuno-peptidomic states, modified peptide presentation, and
IFNγ-STAT1 persistence, thereby linking the visibility axis to
biomarker refinement and visibility-based stratification. PTM,
post-translational modification; IFN, interferon; pMHC,
peptide-major histocompatibility complex.

Figure 4

State constraints, PTM-state and
companion readout modules, assay platforms and treatment-phase
deployment in cancer immunotherapy. This figure summarizes a
constraint-guided framework for biomarker deployment in cancer
immunotherapy. The innermost layer defines three recurrent state
constraints that limit durable antitumor immunity: Checkpoint
competence, tumor visibility, and stress-conditioned immune-state
programming. The intermediate readout layer highlights
representative direct PTM-state, proximal protein-state, and
contextual companion readouts aligned with each constraint. Not all
readouts in this layer directly measure a PTM; transcriptomic,
spatial, cellular and longitudinal features are included as
companion measurements that contextualize functional state. The
outer assay layer organizes the principal analytical platforms
through which these states can be captured in tissue or
longitudinal samples. The figure is intended to guide
discovery-to-validation translation by aligning each constraint
with the readout class, assay layer, and clinical timepoint most
suitable for stratification or monitoring. PTM, post-translational
modification; IHC, immunohistochemistry; IFN, interferon; PD-1,
programmed cell death protein 1; PD-L1, programmed death-ligand 1;
pMHC, peptide-major histocompatibility complex; pHLA, peptide-human
leucocyte antigen; TCR, T cell receptor; LC-MS/MS, liquid
chromatography-tandem mass spectrometry.

Figure 5

Integrated framework of PTM-governed
immune-state regulation in cancer immunity. (A) PTM-state layer
linking protein stability, localization, trafficking, complex
assembly and signaling competence to immune constraints, with
emphasis on protein state beyond abundance. (B) Checkpoint
competence shaped by PTM-dependent stabilization and membrane
persistence of inhibitory checkpoint proteins, particularly PD-L1,
with consequent suppression of T-cell elimination capacity. (C)
Tumor visibility regulated by antigen processing, peptide loading,
antigen-presentation machinery and IFNγ-JAK-STAT signaling. (D)
Stress-driven immune rewiring induced by lactate, reactive oxygen
species, and other tumor-microenvironmental pressures through
glycosylation, ubiquitination, phosphorylation, palmitoylation and
lactylation. (E) Biomarker readout hierarchy integrating contextual
companion information, state-proximal PTM readouts, and clinical
utility. (F) Validation and combination design based on prioritized
or co-dominant immune-state constraints, including
checkpoint-dominant, visibility-deficient, and rewiring-dominant
states. PTM, post-translational modification; PD-L1, programmed
death-ligand 1; IFN, interferon; ROS, reactive oxygen species.
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Copy and paste a formatted citation
Spandidos Publications style
Pan J, Li B, Lin R, Fang C, Lau LY, Hong Z and Chen Y: Post‑translational modification‑governed immune states in cancer immunity: Biomarker implications for checkpoint competence, tumor visibility and immunotherapy resistance (Review). Int J Oncol 69: 119, 2026.
APA
Pan, J., Li, B., Lin, R., Fang, C., Lau, L.Y., Hong, Z., & Chen, Y. (2026). Post‑translational modification‑governed immune states in cancer immunity: Biomarker implications for checkpoint competence, tumor visibility and immunotherapy resistance (Review). International Journal of Oncology, 69, 119. https://doi.org/10.3892/ijo.2026.5932
MLA
Pan, J., Li, B., Lin, R., Fang, C., Lau, L. Y., Hong, Z., Chen, Y."Post‑translational modification‑governed immune states in cancer immunity: Biomarker implications for checkpoint competence, tumor visibility and immunotherapy resistance (Review)". International Journal of Oncology 69.4 (2026): 119.
Chicago
Pan, J., Li, B., Lin, R., Fang, C., Lau, L. Y., Hong, Z., Chen, Y."Post‑translational modification‑governed immune states in cancer immunity: Biomarker implications for checkpoint competence, tumor visibility and immunotherapy resistance (Review)". International Journal of Oncology 69, no. 4 (2026): 119. https://doi.org/10.3892/ijo.2026.5932
Copy and paste a formatted citation
x
Spandidos Publications style
Pan J, Li B, Lin R, Fang C, Lau LY, Hong Z and Chen Y: Post‑translational modification‑governed immune states in cancer immunity: Biomarker implications for checkpoint competence, tumor visibility and immunotherapy resistance (Review). Int J Oncol 69: 119, 2026.
APA
Pan, J., Li, B., Lin, R., Fang, C., Lau, L.Y., Hong, Z., & Chen, Y. (2026). Post‑translational modification‑governed immune states in cancer immunity: Biomarker implications for checkpoint competence, tumor visibility and immunotherapy resistance (Review). International Journal of Oncology, 69, 119. https://doi.org/10.3892/ijo.2026.5932
MLA
Pan, J., Li, B., Lin, R., Fang, C., Lau, L. Y., Hong, Z., Chen, Y."Post‑translational modification‑governed immune states in cancer immunity: Biomarker implications for checkpoint competence, tumor visibility and immunotherapy resistance (Review)". International Journal of Oncology 69.4 (2026): 119.
Chicago
Pan, J., Li, B., Lin, R., Fang, C., Lau, L. Y., Hong, Z., Chen, Y."Post‑translational modification‑governed immune states in cancer immunity: Biomarker implications for checkpoint competence, tumor visibility and immunotherapy resistance (Review)". International Journal of Oncology 69, no. 4 (2026): 119. https://doi.org/10.3892/ijo.2026.5932
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