LAUSR

T cell–directed cancer immunotherapy often fails to generate lasting tumor control. Harnessing additional effectors of the immune response against tumors may strengthen the clinical benefit of immunotherapies. Here, we demonstrate that therapeutic targeting of the interferon-γ (IFN-γ)–interleukin-12 (IL-12) pathway relies on the ability of a population of natural killer (NK) cells with tissue-resident traits to orchestrate an antitumor microenvironment. In particular, we used an engineered adenoviral platform as a tool for intratumoral IL-12 immunotherapy (AdV5–IL-12) to generate adaptive antitumor immunity. Mechanistically, we demonstrate that AdV5–IL-12 is capable of inducing the expression of CC-chemokine ligand 5 (CCL5) in CD49a+ NK cells both in tumor mouse models and tumor specimens from patients with cancer. AdV5–IL-12 imposed CCL5-induced type I conventional dendritic cell (cDC1) infiltration and thus increased DC-CD8 T cell interactions. A similar observation was made for other IFN-γ–inducing therapies such as Programmed cell death 1 (PD-1) blockade. Conversely, failure to respond to IL-12 and PD-1 blockade in tumor models with low CD49a+ CXCR6+ NK cell infiltration could be overcome by intratumoral delivery of CCL5. Thus, therapeutic efficacy depends on the abundance of NK cells with tissue-resident traits and, specifically, their capacity to produce the DC chemoattractant CCL5. Our findings reveal a barrier for T cell–focused therapies and offer mechanistic insights into how T cell–NK cell–DC cross-talk can be enhanced to promote antitumor immunity and overcome resistance. Description A population of CCL5-producing NK cells with tissue-resident traits enhances T cell–DC cross-talk for successful cancer IL-12 immunotherapy. Improving IL-12 immunotherapy Interleukin-12 (IL-12) has been a successful form of cancer immunotherapy in preclinical studies, but its translation has been lacking in early patient clinical trials. To investigate this dichotomy, Kirchhammer et al. used an adenovirus platform to treat patient-derived xenografts intratumorally with IL-12 immunotherapy. They saw that the efficacy of IL-12 treatment was dependent on a population of tissue-associated natural killer (NK) cells that produced the chemoattractant CCL5. They saw that treatment failure could be overcome with an intratumoral delivery of CCL5, suggesting that a potential combination treatment could be useful in patients and warrants further study.