Cancer Drug Patritumab Deruxtecan Triggers Immune System to Attack Tumors

Patritumab deruxtecan is an antibody-drug conjugate (ADC) that pairs a monoclonal antibody targeting HER3 (ERBB3) with the topoisomerase-I inhibitor DXd via cleavable linkers. It has received FDA breakthrough therapy designation for advanced NSCLC progressing after EGFR tyrosine kinase inhibitors and platinum-based chemotherapy. While its direct cytotoxic effects are established, its capacity to engage the immune system via immunogenic cell death (ICD) had not been characterized — until now.

ICD is a specialized form of cancer cell death that releases danger signals (DAMPs) including surface-exposed calreticulin (CALR), secreted ATP, and released HMGB1. These signals recruit and activate dendritic cells, which prime tumor-specific T cells to kill residual cancer cells — effectively turning cell death into an anti-cancer vaccine. The Kroemer/Kepp laboratory at INSERM investigated whether patritumab deruxtecan and its payload DXd could induce this process.

Using human U2OS osteosarcoma cells engineered to express HER3 alongside a CALR-GFP biosensor, the team showed that patritumab deruxtecan selectively decreased viability and induced CALR translocation to the cell periphery only in HER3-expressing cells, not parental controls. Both patritumab deruxtecan and free DXd triggered all three canonical ICD hallmarks: antibody-detectable calreticulin exposure on the cell surface, HMGB1 release into the extracellular space, and ATP secretion into culture supernatants. Additionally, DXd caused rapid inhibition of DNA-to-RNA transcription — identified by nucleolar condensation — which the same group had previously established as an early and predictive biomarker of ICD induction.

To validate ICD in vivo, the researchers treated murine cancer cells with DXd and injected them subcutaneously into immunocompetent syngeneic mice in a prophylactic vaccination model. Vaccinated mice were then rechallenged with live tumor cells. Mice pre-immunized with DXd-treated cells showed significant protection against tumor growth, and tumor-free survivors rejected a secondary rechallenge, demonstrating durable immune memory. These results confirm that DXd functions as a bona fide ICD inducer capable of eliciting protective antitumor immunity in vivo.

These findings are clinically significant because ICD-inducing agents are known to sensitize tumors to immune checkpoint blockade. Patritumab deruxtecan's dual mechanism — targeted cytotoxicity plus immunostimulation — positions it as a candidate for combination with PD-1/PD-L1 inhibitors. However, the in vivo experiments used free DXd rather than the intact ADC, and murine models may not fully replicate human immune responses, so clinical validation remains necessary.