Abstract Cytotoxic anticancer therapies activate programmed cell death in the context of underlying stress and inflammatory signaling to elicit the emission of danger signals, cytokines, and chemokines. In a concerted manner, these immunomodulatory secretomes stimulate antigen presentation and T cell–mediated anticancer immune responses. In some instances, cell death–associated secretomes attract immunosuppressive cells to promote tumor progression. As it stands, cancer cell death–induced changes in the tumor microenvironment that contribute to antitumor or protumor effects remain largely unknown. This is complicated to examine because cell death is often subverted by tumors to circumvent natural, and therapy-induced, immunosurveillance. Here, we provide insights into important but understudied aspects of assessing the contribution of cell death to tumor elimination or cancer progression, including the role of tumor-associated genetics, epigenetics, and oncogenic factors in subverting immunogenic cell death. This perspective will also provide insights on how future studies may address the complex antitumor and protumor immunologic effects of cell death, while accounting for variations in tumor genetics and underlying microenvironment.