Natural compound inducers of immunogenic cell death Abstract Accumulating evidence shows that the anti-cancer potential of the immune response that can be activated by modulation of the immunogenicity of dying cancer cells. This regulated cell death process is called immunogenic cell death (ICD) and constitutes a new innovating anti-cancer strategy with immune-modulatory potential thanks to the release of damage-associated molecular patterns (DAMPs). Some conventional clinically-used chemotherapeutic drugs, as well as preclinically-investigated compounds of natural origins such as anthracyclines, microtubule-destabilizing agents, cardiac glycosides or hypericin derivatives, possess such an immune-stimulatory function by triggering ICD. Here, we discuss the effects of ICD inducers on the release of DAMPs and the activation of corresponding signaling pathways triggering immune recognition. We will discuss potential strategies allowing to overcome resistance mechanisms associated with this treatment approach as well as co-treatment strategies to overcome the immunosuppressive microenvironment. We will highlight the potential role of metronomic immune modulation as well as targeted delivery of ICD-inducing compounds with nanoparticles or liposomal formulations to improving the immunogenicity of ICD inducers aiming at long-term clinical benefits.