Therapy-induced senescence rewires the melanoma secretome to promote antitumor immune response and augment cell therapies.

BACKGROUND

Therapy-induced senescence (TIS) is a common outcome of diverse anticancer treatments, including chemotherapy, radiation, and small-molecule inhibitors. Senescence is characterized by stable growth arrest and the senescence-associated secretory phenotype (SASP), which includes various immune mediators. As the role of the immune system in controlling cancer becomes increasingly appreciated, understanding the impact of TIS on the tumor immune microenvironment (TIME) is critically important. Here, we investigated how senescence can be leveraged to enhance antitumor immune responses.

METHODS

We investigated the effects of an Aurora kinase A inhibitor (AURKAi), a potent inducer of senescence in melanoma models, using transcriptome and secretome profiling. The role of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway was investigated using imaging, inhibitors, and gene knockout. We also examined the effect of AURKAi on the surface expression of major histocompatibility complex class I (MHC-I) and programmed death-ligand 1 (PD-L1), as well as on signal transducer and activator of transcription 1 (STAT1) activation. In vivo, the effects of AURKAi treatment on the TIME were investigated using spectral cytometry and cell depletion studies. Finally, we assessed combining AURKAi with immune checkpoint blockade (ICB), adoptive cell therapy, and natural killer (NK) cell therapy in murine models.

RESULTS

We observed significant gene expression rewiring and the secretion of immune-related mediators and chemokines associated with AURKAi-induced senescence, which was favorably modulated by a senolytic BCL-2/xL inhibitor navitoclax. Mechanistically, AURKAi induced the formation of micronuclei linked with the activation of the cGAS-STING pathway, which, in turn, initiated pro-inflammatory transcriptional programs. Senescent melanoma cells exhibited increased surface expression of MHC-I and PD-L1, along with interferon regulatory factor 3 (IRF3) and STAT1 activation, indicating enhanced immunogenicity. In vivo, AURKAi treatment significantly enriched the TIME with activated CD8+ T cells and NK cells, with depletion studies confirming their critical role in antitumor effects. While combining AURKAi with immune checkpoint blockade was not beneficial, AURKAi pretreatment significantly augmented T and NK cell therapies in murine models, resulting in enhanced tumor control and prolonged survival.

CONCLUSIONS

These findings suggest that senescence, specifically when induced by an AURKAi, can be harnessed to promote effector cell engagement in immune-cold tumors, thereby enhancing responsiveness to cell therapies.