A ribosomal protein-rich tumor cell supernatant as a potent inducer of macrophage polarization for synergistic antitumor chemotherapy.

Abstract

Promoting the M1 polarization of tumor-associated macrophages (TAMs) is a promising strategy to reverse immunosuppressive tumor microenvironment (TME), thereby facilitating tumor treatment. Herein, we develop a tumor treatment approach based on tumor cell supernatant (TCS) prepared via a photodynamic treatment strategy. Strikingly, TCS exhibits a robust ability in inducing the M1 polarization of macrophages compared to two other common types of cell lysates (obtained via freeze-thaw treatment and sonication), and such ability may be attributed to its high content of ribosomal proteins (e.g., 40S ribosomal protein S3), rather than the typical damage-associated molecular patterns (e.g., calreticulin and high mobility group box 1) released from the tumor cells due to the immunogenic cell death induced by photodynamic treatment. Subsequently, TCS is employed to fabricate a hydrogel loaded with a chemotherapeutic drug (denoted as drug@TCS hydrogel; drug = doxorubicin hydrochloride, cisplatin, or 5-fluorouracil). After intratumoral administration, the drug@TCS hydrogel can effectively promote the M1 polarization of TAMs and reverse the immunosuppressive TME, thus exhibiting a prominent tumor growth inhibition capacity. Therefore, such a supernatant may offer an efficacious approach to elevate tumor therapeutic efficacy via the M1 polarization of TAMs, and highlight the immunostimulatory function of the ribosomal proteins released from photodynamic treatment-treated tumor cells.