Patients with inadequate anti-cancer T cell responses experience limited benefit from immune checkpoint inhibitors and other immunotherapies that require T cells. Therefore, treatments that induce de novo anti-cancer T cell immunity are needed. One strategy - referred to as in situ vaccination - is to deliver chemotherapeutic or immunostimulatory drugs into tumors to promote cancer cell death and provide a stimulatory environment for priming T cells against antigens already present in the tumor. However, achieving sufficient drug concentrations in tumors without causing dose-limiting toxicities remains a major challenge. To address this challenge, nanomedicines based on nano-sized carriers ('nanocarriers') of chemotherapeutics and immunostimulants are being developed to improve drug accumulation in tumors following systemic (intravenous) administration. Herein, we present the rationale for using systemically administrable nanomedicines to induce anti-cancer T cell immunity via in situ vaccination and provide an overview of synthetic nanomedicines currently used clinically. We also describe general strategies for improving nanomedicine design to increase tumor uptake, including use of micelle- and star polymer-based nanocarriers. We conclude with perspectives for how nanomedicine properties, host factors and treatment combinations can be leveraged to maximize efficacy.

Fischell Department of Bioengineering A James Clark Hall Room 5110 8278 Paint Branch Drive College Park MD 20742 USA; Avidea Technologies Baltimore MD 21205 USA

Fischell Department of Bioengineering A James Clark Hall Room 5110 8278 Paint Branch Drive College Park MD 20742 USA; United States Department of Veterans Affairs VA Maryland Health Care System 10 North Greene Street Baltimore MD 21201 USA; Robert E Fischell Institute for Biomedical Devices A James Clark Hall Room 5110 8278 Paint Branch Drive College Park MD 20742 USA; Department of Microbiology and Immunology University of Maryland School of Medicine 685 West Baltimore Street HSF 1 Suite 380 Baltimore MD 21201 USA; Marlene and Stewart Greenebaum Cancer Center Executive Office Suite N9E17 22 S Greene Street Baltimore MD 21201 USA

Institute of Macromolecular Chemistry Czech Academy of Sciences Heyrovského nám 2 162 06 Prague Czech Republic

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