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on finding optimal PDT conditions to induce systemic immunity. Recent reports have shown that PDT can
[30]
be an effective adjuvant therapy to surgery that increases the probability of long-term local disease control .
Recently results from a preclinical study have also identified an anti-tumor combined PDT treatment regimen
that controls primary and metastatic tumor growth and enhances anti-tumor immunity of both colon and
[76]
mammary carcinomas . Recently, PDT utilizing the photosensitizer hypericin (Hyp-PDT), became the first
[28]
PDT modality characterized as capable of inducing ICD . Although the immunogenic potential has not
been tested for all PS yet, these recent findings with hypericin constitute an important achievement because
they have allowed PDT to be classified as a therapy capable of inducing ICD. Accordingly, a recent study
have shown that glycoconjugated chlorin-PDT suppressed colon rectal tumor cells (CT26) growth more
efficiently in immunocompetent mice compared with immuno-deficient mice. Additionally, the exposure of
the mice to PDT-treated CT26 cells was capable of protecting them against a subsequent challenge with CT26
cells and this immunogenic effect was dependent on CRT exposure in the plasma membrane and HMGB1
[65]
release, two known features of ICD . Moreover, the increased interest in PDT has actually helped in a deeper
understanding of technical as well as conceptual aspects of ICD and the danger signals involved in this type
of cell death. Further clinical research may perhaps point PDT as a method of vaccination against tumors [78,79] .
This clearly would be of great advantage since PDT in patients treated for primary breast cancer could also
result in increasing acquired immunity against the cancer at distant sites.

Overall, accumulating evidence indicates that the therapeutic efficacy of several antineoplastic agents,
including PDT, relies on their capacity to influence the tumor-host interaction, tipping the balance toward
the activation of an immune response specific for malignant cells, especially for metastasize cancer.

Instrumentation, drawbacks and side effects
PDT has been shown to be effective in treating different types of cancers, especially the ones with superficial
[80]
localizations, as this intervention provides a significant improvement in both the patient’s quality of life
[81]
and its cost-effectiveness compared to palliative surgery or palliative chemotherapy treatments . However,
as happens with other therapies as well, the predominant unfavorable anatomical and microenvironment
conditions have been reported to limit its efficacy and to contribute for the relatively slow transition from
preclinical to clinical practice of PDT for treating these tumors [82,83] . Adjustment of PDT parameters such as
type and local concentration of the PS, light delivery and source or dosimetry in a context where there is no
[84]
homogeneity is considered as one of the bigger obstacles of this therapeutic approach .

The most common concern about the clinical use of PDT constitutes the limited penetration of light.
However, nowadays this old idea that PDT is as a surface treatment because the application of external light
may only treat superficial lesions is no longer believed. This problem is actually in the way of being solved
because of the possibility of using fibers which can be placed in determined locations within the tumor
site. Due to advances in fiber optics and microendoscopic technology, PDT can be used in the clinic with
interstitial, endoscopic, intraoperative or laparoscopic light delivery systems. In this scenario, the laser light
can be adapted into thin optical fibers for delivery of light into deeper and more difficult to access treatment
[85]
sites . These fibers besides being used to deliver light, can also simultaneously act as diagnostic sensors
that can gauge important PDT parameters which critically impact the therapeutic response, such as the
fluence rate, PS concentration, PS photobleaching and the tissue oxygenation status [86,87] . It is important
to take into account that the vascular collapse promoted by PDT can decrease the tumor oxygenation.
Since the success of the treatment relies on the preexisting ground state oxygen to produce singlet oxygen
via type II photochemical reaction [Figure 1], tissue oxygenation state significantly affects the efficiency
of PDT. Moreover during the treatment itself, the formation of ROS using high light fluence rates can
deplete the oxygen levels in tumorigenic tissue too fast, aggravating the tumor hypoxia and hampering the
treatment outcome [40,88,89] . Thus, improvement the oxygen concentration is an important issue for PDT. In
fact, adjusting the light and PS dosimetry, lowering light fluence rates or using light fractionated strategies