Immune therapy-related hyperprogressive disease: Molecular mechanisms, biomarkers, and clinical strategies

Table 1 Incidence, key studies, and risk factors of hyperprogressive disease

Ref.	Cancer type	HPD incidence	Proposed risk factors
Ferrara et al[16], 2018	NSCLC	13.8%-26%	EGFR mutation, LDH > 250 U/L, liver metastasis, ≥ 2 metastatic sites
Lo Russo et al[14], 2020
Economopoulou et al[17], 2021	HNSCC	15.4%	11q13 chromosomal amplification (CCND1/FGF3), local recurrence
Kim et al[18], 2022	GC	9.2%-29.4%	EGFR/FGF4, MDM2 amplification, liver metastasis, high tumor burden, advanced age
Aoki et al[19], 2024
Hwang et al[22], 2020	Urothelial carcinoma	6.4%-8%	Elevated baseline NLR, high LDH levels
Abbas et al[10], 2019
Yamada et al[13], 2018	Melanoma	6%-42%	Advanced age, elevated baseline inflammatory markers (CRP/NLR)
Zhou et al[20], 2025
Şen et al[21], 2024	Bladder cancer	12.9%	Elevated baseline NLR, advanced age
	Renal cell carcinoma	4.8%

HPD: Hyperprogressive disease; NSCLC: Non-small cell lung cancer; HNSCC: Head and neck squamous cell carcinoma; GC: Gastric cancer; EGFR: Epidermal growth factor receptor; LDH: Lactate dehydrogenase; CCND1: Cyclin D1; FGF3: Fibroblast growth factor 3; FGF4: Fibroblast growth factor 4; MDM2: Mouse double minute 2 homolog; NLR: Neutrophil-to-lymphocyte ratio; CRP: C-reactive protein.

Table 2 Key regulatory mechanisms and therapeutic strategies in hyperprogressive disease

Regulatory factor	Core mechanism	Clinical significance	Potential intervention strategies
Treg cells	Abnormal activation post PD-1 blockade; inhibits APC function via CTLA-4/CD80/CD86; secretes IL-10/TGF-β to suppress effector T cells	Significant Treg infiltration in HPD patients, negatively correlated with treatment efficacy	Target CTLA-4 or deplete Tregs (e.g., anti-CCR4 antibodies)
M2-type TAM	Fc receptor-mediated pro-tumor phenotype conversion by anti-PD-1; recruited via CCR2/CCL2 and maintained by CSF-1R signaling	Forms synergistic network with Tregs/MDSCs to drive HPD	Combine CSF-1R inhibitors with PD-1 blockade (e.g., pexidartinib)
MDSC	Suppresses T cell function via IDO/VEGF/MMP9; promotes angiogenesis	High MDSC levels predict poor ICI response and HPD risk	Target CXCR2 or arginine metabolism (e.g., CB-1158)
T cell exhaustion	Compensatory upregulation of TIM-3/CTLA-4 post PD-1 blockade, leading to “secondary exhaustion”	Enriched in HPD patients with lost anti-tumor function	Multi-checkpoint targeting (e.g., anti-TIM-3 + anti-PD-1)
CAF	Upregulates PD-L1 via IL-6/STAT3; recruits Tregs via CXCL12; promotes M2-TAM differentiation	Promotes immunosuppressive microenvironment, positively correlated with HPD progression	Target TGF-β signaling (e.g., galunisertib) or CAF reprogramming
Inflammatory dysregulation	IL-10 inhibits CD28 signaling; IFN-γ induces PD-L1 upregulation; IL-6/TNF-α activate STAT3/NF-κB to promote proliferation	Cytokine profile predicts HPD risk	JAK inhibitors (e.g., ruxolitinib) or IL-6R blockade (tocilizumab)
Metabolic reprogramming	Tregs utilize lactate/OXPHOS for survival; CD36 mediates fatty acid metabolism adaptation	Metabolic competition exacerbates T cell dysfunction	Lactate dehydrogenase inhibitors or CD36 blockade
Genetic alterations	MDM2/MDM4 amplification (p53 degradation); EGFR activation (PD-L1 modification); DNMT3A mutations (epigenetic dysregulation)	11-gene mutation signature significantly associated with HPD	MDM2 inhibitors (e.g., idasanutlin) or EGFR-TKI combination therapy

TAM: Tumor-associated macrophages; Tregs: Regulatory T cells; APC: Antigen-presenting cell; MDSC: Myeloid-derived suppressor cell; CAF: Cancer-associated fibroblasts; CTLA-4: Cytotoxic T-lymphocyte-associated protein 4; IL-10/TGF-β: Interleukin-10/transforming growth factor-beta; HPD: Hyperprogressive disease; CCR4: C-C chemokine receptor type 4; CCR2: C-C chemokine receptor type 2; CCL2: C-C chemokine ligand 2; CSF-1R: Colony-stimulating factor 1 receptor; MDSCs: Myeloid-derived suppressor cells; ICI: Immune checkpoint inhibitors; PD-1: Programmed death receptor-1; CXCR2: C-X-C chemokine receptor type 2; CB-1158: Arginase inhibitor; TIM-3: T cell immunoreceptor with Ig and ITIM domains; STAT3: Signal transducer and activator of transcription 3; IDO: Indoleamine 2,3-dioxygenase; VEGF: Vascular endothelial growth factor; MMP9: Matrix metalloproteinase 9; CXCL12: C-X-C chemokine ligand 12; M2-TAM: M2-type tumor-associated macrophages; IFN-γ: Interferon-gamma; PD-L1: Programmed death-ligand 1; TNF-α: Tumor necrosis factor-Alpha; NF-κB: Nuclear factor-kappa B; OXPHOS: Oxidative phosphorylation; MDM2: Mouse double minute 2 homolog; EGFR-TKI: Epidermal growth factor receptor-tyrosine kinase inhibitor.