?In most cancers, tumor metastasis is an extremely important factor in determining the survival of patients. Historically, radiotherapy (rt) for primary tumors has rarely been associated with the relief of metastasis in areas other than radiotherapy. This phenomenon of away from the target area or "distance effect" has attracted attention because of its rareness.

?With the advent of immunotherapy, the dissociation effect after rt combined with immune checkpoint inhibition is increasingly reported. This has triggered investigations of potential mechanisms and clinical trials aimed at enhancing this effect. While these studies clearly attribute the dissociation effect to the anti-tumor immune response, its occurrence and specificity of the initial molecular trigger remains a mystery.

?This paper proposes that DNA damage-induced inflammation combined with neoantigens production is essential in this interesting phenomenon of systemic tumor regression, and discusses the significance of this model for treatment aimed at triggering the distancing effect of metastatic cancer.

?British scientist Robinmole proposed in 1953 the concept of the distancing effect of "a certain distance from the irradiated volume will have an effect". This term was later adopted by oncologists, who described very rare cases of metastasis relief in non-radiotherapy fields since the 1970s.

?A systematic literature search was conducted and it was estimated that no more than 47 reported cases describing the distant effects of radiotherapy by 2014. This number increased significantly with the combined application of immune checkpoint inhibition (ici) therapy with RT. Several attempts have been made to quantify the probability of distant effects. For example, a non-randomized study analysis of 10 patients with metastatic melanoma between 2014 and 2019 showed distant tumor remission in 34.3% of cases (18%63%, 62 showed distant effects). Between 2009 and 2017, a similar meta-analysis was conducted on eight metastatic melanoma studies, reporting an average of 26.5% of cases (range between 10%-63%; 65 total cases showed distant effects).

? Despite these encouraging observations, the incidence of distancing effects against rt/ici is still needed to be randomly examined in order to finalize the frequency of this phenomenon. In fact, in 32 cases of metastatic squamous cell carcinoma of the head and neck, a randomized trial of rt/ici showed no significant effect in 0 cases (9 cases). Several upcoming randomized trials of combined rt and                                                                                                                                                                                                           �

?With the introduction of ici, there are more cases of documented dissociation effect, but these cases may be limited to a small number of patients, and may even be limited to specific cancer types. Consistent with this, many documented dissociation effects have occurred in melanoma and lung cancer, often showing higher rates of lymphocyte infiltration and mutation. These emerging data suggest that rt/ici therapy is especially suitable for immunogenic cancer subtypes, as this may better achieve dissociation effect.

?Since recognizing this, an increasing focus has been on determining clinical parameters and treatment conditions to promote systematic response to DNA damage therapy. Retrospective analysis showed that inguinal tumor regression was associated with increased infiltration of cd8 cytotoxic T lymphocytes (CTL) and decrease in cd8Foxp3 regulatory T cells (Treg). The incidence of dissociation effect was also negatively correlated with lymphocytopenia. However, high doses of RT were associated with depletion of immune cells in patients. Consistent with this, one observation was that fractionated RT was clinically associated with dissociation effect. In addition, administration of highly targeted RT through procedures such as sbrt can further protect patient lymphocytes and promote dissociation effect.

?The role of RT segmentation has been studied in preclinical mouse models. It has been found that RT is conducive to tumor regression at distant sites within at least two treatment cycles, while a single high dose of RT is conducive to Treg differentiation and therefore may promote tumor progression. Targeted clinical trial design RT protocols are needed, which are conducive to the remission of specific cancer types.

The patient showed a distant effect when RT did not consume all lymphocytes, the ctl/treg ratio was good, and immune stimulation was achieved through segmented RT.

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