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Ceramide Disrupts TM9SF2-PGK1 Axis to Redirect PD-L1 Trafficking and Enhance Antitumor Immunity

ABSTRACT:

The PD-1/PD-L1 axis represents a cornerstone of cancer immunotherapy, yet the dynamic shuttling of PD-L1 between endosomal recycling and lysosomal degradation routes limits durable responses. Using a CRISPR screen targeting glycosphingolipid metabolism, we identify TM9SF2 as a key regulator of PD-L1 levels. TM9SF2 orchestrates a dual mechanism: it recruits PGK1 to promote PD-L1 recycling to the plasma membrane while dismantling the HIP1R-mediated lysosomal degradation pathway. Genetic or pharmacological disruption of the TM9SF2-PGK1 complex depletes PD-L1 levels and boosts antitumor immunity. Further, the endogenous ceramide species Cer(d18:1/26:0) destabilizes this complex, triggering PD-L1 lysosomal destruction and potentiating antitumor immunity. These findings delineate a ceramide-gated sorting mechanism within the endosomal network, revealing a druggable metabolic switch to disrupt immune evasion and amplify checkpoint blockade efficacy.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse-phase, Liquid Chromatography MS - positive - reverse-phase

PROVIDER: MTBLS13838 | MetaboLights | 2026-02-05

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS13838_LC-MS_negative_reverse-phase_metabolite_profiling.txt	Txt
	a_MTBLS13838_LC-MS_positive_reverse-phase_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS13838_LC-MS_negative_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular
	m_MTBLS13838_LC-MS_positive_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular

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