Figure 9. Cooperative and complimentary mechanisms for synergy between SMCs and ICI.

(1) The presence of therapeutic recombinant antibodies that block the PD-1/PD-L1 axis allows for signalling of the TCR of a CD8⁺ T-cell with its associated antigen presented by the cancer cell through a MHC-I molecule. Concurrent depletion of the IAPs through SMC treatment can enhance T-cell activation, likely by providing a tumour necrosis factor receptor superfamily (TNFRSF) co-stimulatory response (similar to 4-1BB or OX40 activation), resulting in enhanced activation and expansion of tumour-specific CD8⁺ T-cells. As a result, Granzyme B (GrzB) and Perforin (Pfn) are secreted to kill target cells. (2) SMC-mediated antagonism of the casp-3 inhibitor, XIAP, can result in enhanced death of tumour cells by GrzB. (3) The depletion of cIAP1 and cIAP2 by SMCs leads to increased local production of TNF-α by T-cells in the tumour microenvironment, an effect that is likely mediated by activation of the alternative NF-κB pathway. (4) As a result of cIAP1/ 2 loss, SMC-treated cancer cells are sensitized to cell death induction in the presence of proinflammatory cytokines, such as TNF-α.