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proteins. After internalization, most of the PSs are localized in organelle membranes due to their common
chemical core. In general, PS’s cellular localization can be highly specific or quite broad, and have been
reported to include the endoplasmic reticulum (ER), mitochondria, Golgi complex, lysosomes and the
plasma membrane [40,55] . To limit DNA damage and avoid the development of genetically resistant cells, PS
[30]
should not accumulate in the cell nuclei . Accidental necrosis is more often observed when the PS site of
[40]
action is in the plasma membrane and/or when it is activated with high energy doses . In order to suppress
[56]
undesired damage to normal tissues, this effect should in general be avoided . In an organelle-specific
photodamage scenario, the mechanism of autophagy is activated as a coordinated intracellular response
aiming at reestablishing homeostasis. When impaired or insufficient autophagy is triggered, induction of cell
death is the most common result observed [26,38,57,58] . The best documented organelle specific cytotoxic effects
of PDT are related with the photodamage of mitochondria, lysosomes and ER.

Porphyrins can present a variable localization pattern, mostly associated with plasma membranes and
mitochondria. PSs that are located in the mitochondria can cause mitochondrial inner membrane
permeabilization and selectively damage antiapoptotic proteins of the BCL-2 family, localized at the outer
mitochondrial membrane while the proapoptotic proteins are left intact, resulting in an unbalance of pro-
[35]
and anti-apoptotic players that results in caspase activation . On the other hand, some mitochondria-
[59]
associated porphyrins can also activate necroptosis, as already shown in 5-ALA-PDT) . A lysosome
localization pattern was observed using negatively-charged porphyrins, NPe6 and the phenothiazinium
methylene blue [26,38,53] . A potential advantage of lysosome target PDT is that lysosomal damage might easily
circumvent autophagic protection that can be activated in parallel of cell damage. Lysosome damaging PDT
leads to LDCD [39,51,60] . Release of cathepsins after PDT can result in cleavage of the pro-apoptotic protein Bid
to a truncated form termed tBid. This product can in turn interact with mitochondria, leading to the release
of cytochrome c, followed by the consequent activation of intrinsic apoptosis as already shown in NPe6-
PDT . However, not only apoptosis can be activated by lysosome damage and although it has not been
[41]
demonstrated as a PDT-induced mechanism yet, several parameters of regulated necrosis have been also
[61]
associated with LDCD. Indeed, the degradation of caspase-8 and recruitment of necroptosis machinery
or even the involvement of iron homeostasis modulation leading to an increased susceptibility to undergo
ferroptosis have already been associated with lysosomal damage. Other porphyrins such as mTHPC and
[62]
Hypericin, have been reported to target ER or both ER and mitochondria. Under massive photodamage in
ER membranes, PDT can elicit pro-death signaling via the unfolded protein response cascade. The resulted
ER stress, activates the pro-apoptotic transcription factor CHOP, which in turn mediates mitochondrial
[63]
apoptosis . The induction of multiple cell death pathways is usually considered as an useful characteristic
[64]
of PDT, since it increases photokilling in tumor cells harboring a particular cell death pathway resistance .
PDT and immune response as a tool to deal with metastasis
The major challenge in the fight against cancer includes treatment toxicity and drug-resistance associated
with incompletely tumor removal by surgical resection. In order to extend patient survival, systemic
chemotherapy has become an essential part of treatment after surgery. However, therapies effective in
both reducing the high mortality rate associated with the disease as well as improving patient quality of
life still need to be developed [22,35] . In an attempt to circumvent the appearance of a secondary disease,
immunotherapy has been applied and developed as a tool to control cancer recurrence and metastases.
There are few effective treatments for metastases, thus there is an increased interest in therapies that
eliminate primary tumors and systemically activate antitumor immune responses. In this sense, PDT
emerges as a potential therapy to be used alone or in combination with other approved or experimental
[65]
approaches because of the recent findings indicating that PDT can also trigger systemic effects, including
the reinstallation of immunosurveillance [29,66] .

Examples of immunotherapy include the use of monoclonal antibodies to block immune checkpoint activity
of cancer cells, enabling anti-cancer T cell responses, or adoptive cellular therapy to prime patient’s own