Targeted T cell immunotherapies, most prominently chimeric antigen receptor T (CAR-T) therapy, have led to a transformation in the treatment of hematologic and subsets of solid tumors. Despite the success of CAR-T therapy, relapse frequently occurs due to antigen-escape, where tumors no longer express the targeted antigen. The following dissertation expands on previous findings that the Fas-signaling pathway plays a critical role in on-target and antigen-independent killing of tumor cells, a phenomenon known as “bystander killing”. Our first studies demonstrate that CART bystander killing occurs in an Ag-dependent and Fas-dependent fashion, which relies on FasL expression on CAR-T cells and not on soluble factors. Importantly, we demonstrate that Fasdependent bystander killing occurs within a lymphoma mouse model and leads to survival benefit. We use microwell live imaging to characterize the spatiotemporal limitations of CAR-T bystander killing in order to understand how it can be optimally applied. Next, we sought to enhance Fas signaling in tumor cells, and discovered that antagonizing the inhibitor of apoptosis (IAP) family of proteins could synergize with CAR-T bystander killing. We reasoned that increased CAR-T FasL expression could also improve bystander killing, which we demonstrate with inhibition of ADAM10 metalloproteinase and by expressing a non-cleavable FasL on CAR-T. Finally, we expand the scope of CAR-T bystander killing by targeting tumor-associated macrophages to elicit bystander killing of tumor cells. We show that IAP antagonism leads to potent bystander killing with CAR-T and bispecific antibody. Future work will focus on translating these findings in vivo and to patients with Fas-expressing tumors.