Fig. 2

SASP into the different steps of cancer immunoediting

(A) Cancer immunoediting is a dynamic process between tumor cells and the immune system and it has been outlined in the 3Es. In the first phase of elimination, innate and adaptive immunity destroys developing tumors before they become clinically evident. If this step is performed successfully the tumor cells are removed. If, however, the tumor cell variants are not destroyed, the equilibrium phase can be entered, in which tumor growth is confined by immunological mechanisms in a state of functional dormancy. In this phase tumor cell variants may emerge as a consequence of constant immune selection pressure and may enter into the escape phase, in which their growth is no longer blocked by immunity and tumor becomes clinically detectable. (B) SASP can lead to the clearance or the protection of cancer cells, favoring cell dormancy and tumor recurrence. In the “elimination phase” SnCs are efficiently eliminated by both innate and adaptive immune cells. Initially SASP released by oncogene-induced senescent tumor cells can recruit immune cells into the tumor bed favoring the elimination of cancer cells. During this phase some cancer cells may remain and contribute to the establishment of an equilibrium between the tumor and the immune system. In this “equilibrium phase 1”, the immune system holds the tumor in a state of functional dormancy and senescent cells may contribute by releasing a plethora of different factors conditioning the TME. During this phase there is a balance between anti-tumor and tumor promoting cytokines and due to constant immune pressure, tumor cell variants evolve that resist immune recognition and drive the following “escape phase”. As a further layer of complexity some variants that have acquired the ability to metastasize leave the primary tumor (“equilibrium phase 2”), and senescent tumor cells can be found within metastatic lesions. In the “escape phase” senescent tumor cells release a pro-inflammatory SASP and may re-entry into the cell cycle contributing to a clinically detectable tumor that can be treated by therapy. Following treatment, a new “equilibrium phase 3” can be achieved in which it is possible to observe a residual tumor mass. The final use of senotherapy can lead to complete recovery.

Abbreviation: TRM (Tissue resident memory cells); MDSC (Myeloid-derived suppressor cells)

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