Enhanced antitumor immunity in breast cancer: Synergistic effects of ADAM10/ADAM17 inhibition, metabolic modulation, and camptothecin-loaded selenium nanoparticles

In this study, we investigate the impact of a multi-targeted therapeutic approach that includes camptothecin (CPT), a potent chemotherapeutic topoisomerase inhibitor; metformin (Met), a metabolic modulator with emerging anti-tumor effects; and GW280264X, an inhibitor of ADAM 10/ADAM 17 enzymes, which are associated with tumor invasion and immune response. The study aims to assess the combined effects of these agents in enhancing CD8⁺ T cell-mediated anti-tumor immunity and suppressing cancer cell growth in triple-negative breast cancer (TNBC) models, both in vitro and in vivo.

Cell viability was performed on the 4 T1 human TNBC cell line. Furthermore, we examined c-MYC protein expression by western blot, TOX and NR4A expression by Real-time PCR, and the number of CD8⁺ CD28⁺ T cells by immunofluorescence assay to demonstrate the anticancer effects of combined of CPT, Met and GW280264X in BC growth, exhaustion and senescence of T cells.

Regarding cell viability, HA-Se@CPT + Met and HA-Se@CPT + Met + GW280264X treatments decreased 4 T1 cell growth (p < 0.001). Combination therapy of Met, HA-Se@CPT, and GW280264X significantly reduced tumor volume and weight in vivo. This treatment also increased the number of CD8⁺ CD28⁺ T cells in the tumor microenvironment (TME) of BC (p < 0.0001) and decreased the expression of TOX and NR4A (p < 0.0001, p < 0.01). Furthermore, decreased expression of c-MYC as an oncogene protein was seen in the single and combined treatment by HA-Se@CPT and GW280264X (p < 0.05).

These findings suggest that of HA-Se@CPT, Met, and GW280264X may inhibit tumor progression in BC by improving the function and infiltration of CD8⁺ T cells. Their effect is more pronounced when used in combination.