Cross-priming underlies the efficacy of antibody-drug conjugates and immunotherapy combinations.

Antibody-drug conjugates (ADCs) selectively deliver potent chemotherapeutic agents to tumor cells. In clinical settings, the therapeutic benefits of ADCs can be improved when combined with immune checkpoint inhibitors, probably due to the immunogenic nature of ADC-induced tumor cell death, which releases tumor antigens to be cross-presented by conventional type-1 dendritic cells (cDC1). This opinion article proposes that cDC1-mediated cross-presentation and cross-priming represent a central, still poorly understood, and underexploited immunological mechanism that links ADC-induced tumor cell death to durable antitumor immunity. Such mechanisms open opportunities for combinations with established and experimental immunomodulatory agents. Aside from checkpoint inhibitors, synergy has also been observed with agonist monoclonal antibodies directed to costimulatory receptors, increasing the potency of the ensuing antitumor immune response.