Mechanisms regulating combination effect of antibody-drug conjugates and cancer immunotherapy
Antibody–drug conjugates (ADCs) have emerged as a transformative class of cancer therapeutics with important challenges still to be addressed. Combination of ADC with immunotherapy is a promising strategy but mechanisms and effective application remain to be determined. We evaluated ADC combinations with T cell engagers (TCEs) and checkpoint inhibitors (CPI). ADC–TCE combinations produced robust antitumor activity independent of antigen and payload and persisted despite ADC-related T cell loss. Efficacy was dominated by a direct effect of ADC on tumor cells. ADCs induced autophagy that upregulated TNF receptors (TNFRs) and mannose-6-phosphate receptors (M6PR). When ADCs were combined with TCEs TNFα released by T cells was primarily responsible for potent antitumor effect of combination. In contrast, M6PR was dispensable for ADC–TCE activity but critical for combinations with CPI expanded antigen-specific T cells via enhanced granzyme B uptake. These data reveal a unifying, target- and payload-agnostic mechanism enabling rational ADC–immunotherapy combinations. Significance This is first evidence that ADC-induced tumor cell autophagy via up-regulation of TNFR and M6PR could be responsible for potent antitumor effect of combination of ADC with TCE. TCEs exploit a TNFα–TNFR axis, whereas antigen-specific T cells leverage granzyme B–M6PR uptake. This mechanistic framework explains broad ADC–TCE synergy and guides rational selection of ADC–immunotherapy combinations beyond checkpoint blockade.