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All-trans retinoic acid in solid-tumour immunity: context-dependent signalling, cellular states, and combination therapy

Year: 2026
Type: review
Abstract: All-trans retinoic acid (ATRA) influences several processes relevant to cancer immunotherapy, yet its effects in solid tumours range from relief of myeloid suppression to reinforcement of immune tolerance. This divergence reflects the source and duration of retinoid exposure, the molecular state of responding cells and the phase of treatment. We examine these determinants across myeloid, tumour-cell, lymphoid and stromal compartments, distinguishing administered ATRA and ATRA-containing formulations from locally produced retinoic acid (RA) and interventions targeting the RA pathway. Local synthesis and CYP26-mediated catabolism regulate availability, whereas intracellular binding proteins, RAR/RXR complexes, transcriptional coregulators and chromatin influence the response to that exposure. Interactions with interferon, TGF-β, IL-10 and PD-L1 further connect retinoid signalling to immune recognition, regulation and adaptive resistance. Experimental studies support distinct combination strategies based on myeloid differentiation, tumour-cell recognition, preservation of effector function and stromal reprogramming. Human immunotherapy studies show pharmacodynamic activity and combination feasibility, with mixed clinical results across uncontrolled and comparative cohorts. We propose that translation should prioritise a defined, reversible barrier to immunity, pair blood measurements with functional tumour sampling, and compare ATRA-containing treatment with the same partner regimen alone. This approach gives context dependence a testable basis and directs ATRA development towards biologically selected combinations.
DOI: 10.3389/fimmu.2026.1953814
Language: English
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7223047059
FWCI:
Cites: 116
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Related to: 10