Neutrophils can efficiently trigger cytotoxicity towards tumor cells and other target cells upon engagement of the IgA receptor CD89. However, the cell-intrinsic factors that influence the induction of cell death upon exposure to neutrophil effector mechanisms in vivo remain largely unknown. To uncover genetic regulators that influence target cell sensitivity to IgA-induced neutrophil-mediated killing, we used a human CD89 (hCD89) transgenic mouse model in which IgA-mediated killing of Her2-positive CD47-deficient murine target cells is mediated by neutrophils. Using a genome-wide in vivo screening approach, we demonstrate that deletion of the gene encoding inositol-tetrakisphosphate 1 kinase, ITPK1, increases survival of target cells in anti-Her2 IgA-treated mice. Moreover, we show that this effect depends on neutrophil activity and on the ITPK1 kinase domain. Notably, ITPK1 deficiency did not measurably impact survival of IgA-opsonized target cells in in vitro systems, underscoring the importance of in vivo screening systems to uncover physiologically relevant regulators of neutrophil killing. Overall design: Three separate cultures of Ba/F3 cells were harvested, and washed once in PBS. RNA was subsequently extracted using the RNeasy Mini Kit (Qiagen #74004), according to the manufacturer’s instructions. Samples were processed using the TruSeq Stranded mRNA Kit (Illumina #20020594) for whole transcriptome sequencing. Samples were multiplexed and sequenced (50bp, single-end) on an Illumina NovaSeq6000 system (S1 flow cell). Reads were aligned to the reference genome (GRCm38, pre-built HISAT2 index, genome_snp_tran), and transcript counts were obtained using an in-house generated pipeline (GenSum, https://github.com/NKI-GCF/gensum).