Key methods and results from Zhu et al. . a Primary NK cells (blue) were co-cultured with cancer cells (gray) on a microscope stage. The blue color indicates a NK cell that is not yet activated. The red circles are cytotoxic granules which are not yet polarized towards the target cell. Granules were imaged using a dye that accumulates in acidic compartments. b If the NK cell detected an activating balance of ligands on the target cell surface, it committed to killing the target, illustrated by the yellow color. Cytotoxic granules then move towards the target cell on microtubules prior to directed secretion into the immunological synapse. c Granzyme-induced apoptosis is the canonical cell-killing pathway for both NK and T cells. It is typically induced when granzyme B cleaves and activates caspase 3 in the target cell. The red gradient indicates uptake of granzymes by the target cell. Granzyme B activity was monitored using a fluorescent biosensor. Apoptosis was monitored using a reporter of mitochondrial outer membrane permeabilization (MOMP). d Granzyme-independent apoptosis is a well-characterized cell killing pathway that is triggered by death receptor ligands expressed by the NK cell. It was scored by apoptosis that occurred in the absence of granzyme B activation and did not require granule secretion. e Granzyme-dependent necroptosis is a novel cell killing pathway. It was scored by large, sparse blebs on the target cell, lack of MOMP, dependence on cytotoxic granule secretion, granzyme B activity, and expression of RIP1, RIP3, and MLKL. The green bar indicates the assembly of MLKL-dependent pores at the base of a bleb, which is the execution step in necroptosis. Necroptosis blebs are distinguished from apoptosis blebs by their larger size, much smaller number per cell and lack of rapid inflation-retraction dynamics.