Bystander effects in photodynamic therapy-treated tumors involve spatiotemporally extended ferroptosis

The tumor bystander effect describes the ability of cells sustaining therapeutic treatment damage to transmit distress signals to neighboring unharmed cells and change their behavior. Photodynamic therapy (PDT), which uses light for activation of photosensitizing drugs in targeted lesions to produce cytotoxic damage, is one of the cancer treatment modalities inducing highly robust bystander effects. This is caused to a large extent by the propensity of PDT for creating extensive lipid peroxidation damage and related instigation of ferroptotic cell death. Lipid peroxides appear to be major participants in intercellular signaling generating the bystander effect and orchestrating ferroptosis that appears to have a pivotal role in propagating the lethal (therapeutically beneficial) form of bystander response. In contrast, nitric oxide (NO) released from PDT-treated cancer cells has emerged as a major signal for therapeutically detrimental bystander effects due to promoting tumor growth and metastasis. It is becoming increasingly evident that exploiting the bystander response can be an attractive strategy for improving tumoricidal depth with consequently elevated tumor cure rates following PDT treatment. A two-pronged approach is proposed for achieving this goal: (i) inactivating iNOS enzyme with a specific pharmacologic inhibitor, and (ii) amplifying the induction of cytotoxic ferroptosis in nearby cells initially unaffected by photodamage, thereby limiting their ability to promote tumor expansion.