Pharmacological reprogramming of myeloid suppression in solid tumors: mechanisms, evidence standards for immune conversion, and biomarker-informed combinations
- 1Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad
- 2Clinic of Dermatovenereology, University Clinical Center of Vojvodina
- 3Clinic for Eye Diseases, University Clinical Center of Vojvodina
Abstract
Myeloid cells regulate immune exclusion, T-cell dysfunction, angiogenesis, stromal remodeling, and resistance to immune checkpoint blockade in solid tumors. Pharmacological development has moved from nonspecific depletion toward recruitment or survival blockade, intracellular state reprogramming, restoration of antigen presentation, and tumor-selective phagocytosis. Clinical experience nevertheless shows a recurrent gap between biological activity and attributable therapeutic immune conversion. We introduce the Myeloid Immune Conversion Audit Trail (MICAT), a fixed four-level extension of the pharmacological audit trail that grades intratumoral target engagement, conversion of the intended myeloid state, propagation through the immune ecosystem, and randomized clinical attribution. Each level is scored as not demonstrated, partial, or demonstrated. Applying MICAT across representative trials shows that most programs stop at systemic pharmacodynamics or partial lineage effects; few establish ecosystem propagation, and none yet completes the entire causal chain for an immunological switch in a solid-tumor carcinoma. The analysis identifies compensation and redundancy as the central biological obstacle: CCR2 blockade can recruit CXCR2-positive neutrophils, CSF1R inhibition can spare resistant SPP1-high macrophages, and CD40 or PI3Kγ activation can induce interferon-linked PD-L1 feedback. We therefore prioritize lineage-resolved paired tissue, preservation of cDC1 and cDC2 function, absolute cell quantification, orthogonal functional and spatial readouts, and randomized component-controlled trials. Disease context is decisive: tenosynovial giant-cell tumor establishes CSF1R dependence without proving immune conversion; macrophage-rich triple-negative breast cancer is a rational PI3Kγ test-bed; pancreatic ductal adenocarcinoma permits sequence-aware CD40 and stromal studies; and microsatellite-stable colorectal cancer is a stringent failure benchmark. CAR-macrophages, in vivo mRNA/lipid-nanoparticle reprogramming, myeloid engagers, and artificial-intelligence-assisted spatial scoring are mapped to the same evidence requirements. MICAT is intended as a reproducible tool for pharmacological go/no-go decisions rather than a claim that target modulation alone constitutes therapeutic immune conversion.
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BibTeX
@article{maletin2026pharmacological,
title = {{Pharmacological reprogramming of myeloid suppression in solid tumors: mechanisms, evidence standards for immune conversion, and biomarker-informed combinations}},
author = {Nemanja Maletin and Nikola Denda and Milica Paut Kusturica and Aleksandar Rašković and Siniša Babović and Zoran Golušin},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1986842},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1986842/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Pharmacological reprogramming of myeloid suppression in solid tumors: mechanisms, evidence standards for immune conversion, and biomarker-informed combinations
AU - Nemanja Maletin
AU - Nikola Denda
AU - Milica Paut Kusturica
AU - Aleksandar Rašković
AU - Siniša Babović
AU - Zoran Golušin
PY - 2026
DA - 2026/10/20
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1986842
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1986842/full
AB - Myeloid cells regulate immune exclusion, T-cell dysfunction, angiogenesis, stromal remodeling, and resistance to immune checkpoint blockade in solid tumors. Pharmacological development has moved from nonspecific depletion toward recruitment or survival blockade, intracellular state reprogramming, restoration of antigen presentation, and tumor-selective phagocytosis. Clinical experience nevertheless shows a recurrent gap between biological activity and attributable therapeutic immune conversion. We introduce the Myeloid Immune Conversion Audit Trail (MICAT), a fixed four-level extension of the pharmacological audit trail that grades intratumoral target engagement, conversion of the intended myeloid state, propagation through the immune ecosystem, and randomized clinical attribution. Each level is scored as not demonstrated, partial, or demonstrated. Applying MICAT across representative trials shows that most programs stop at systemic pharmacodynamics or partial lineage effects; few establish ecosystem propagation, and none yet completes the entire causal chain for an immunological switch in a solid-tumor carcinoma. The analysis identifies compensation and redundancy as the central biological obstacle: CCR2 blockade can recruit CXCR2-positive neutrophils, CSF1R inhibition can spare resistant SPP1-high macrophages, and CD40 or PI3Kγ activation can induce interferon-linked PD-L1 feedback. We therefore prioritize lineage-resolved paired tissue, preservation of cDC1 and cDC2 function, absolute cell quantification, orthogonal functional and spatial readouts, and randomized component-controlled trials. Disease context is decisive: tenosynovial giant-cell tumor establishes CSF1R dependence without proving immune conversion; macrophage-rich triple-negative breast cancer is a rational PI3Kγ test-bed; pancreatic ductal adenocarcinoma permits sequence-aware CD40 and stromal studies; and microsatellite-stable colorectal cancer is a stringent failure benchmark. CAR-macrophages, in vivo mRNA/lipid-nanoparticle reprogramming, myeloid engagers, and artificial-intelligence-assisted spatial scoring are mapped to the same evidence requirements. MICAT is intended as a reproducible tool for pharmacological go/no-go decisions rather than a claim that target modulation alone constitutes therapeutic immune conversion.
SN - 1663-9812
ER -