ER stress, autophagy and immunogenic cell death in photodynamic therapy-induced anti-cancer immune responses

Tumours are a form of pseudo-organs with their own microenvironment where the cancer cells nurture a dysfunctional immune environment incapable of inciting anti-tumour immunity. It had been proposed that the only way to counteract such an immune system dysfunction in tumours is by eliciting, therapeutically, a cancer cell death pathway that is accompanied by high immunogenicity and possibly inhibits or reduces the influence of the pro-tumourigenic cytokine signalling. Subsequently, a small and a large-scale screening study as well as several targeted studies found that few, selected anticancer therapeutic regimens are able to induce a promising kind of cancer cell demise called immunogenic cell death (ICD), which can activate the immune system owing to the spatiotemporally defined emission of danger signals. Recently, photodynamic therapy (PDT) utilizing the photosensitiser, hypericin (Hyp), became the first PDT paradigm characterized to be capable of inducing bona fide ICD. In the present perspective, we discuss the various technical, conceptual, and molecular advancements and unprecedented results revealed by Hyp-PDT that have influenced the fields of ICD, ER stress biology, cancer cell death, anti-cancer immune responses, photoimmunology and PDT.