Macrophage reprogramming from tumor-supportive to suppressive, pro-inflammatory phenotypes via nanoparticles is emerging as a powerful strategy against immunologically “cold” cancers such as non-small cell lung cancer (NSCLC). Rod-shaped plant viruses represent a particularly attractive nanoparticle platform, with precisely tunable structures, for modulating macrophages and their interactions with cancer cells. Established platforms such as tobacco mosaic virus (TMV) show potential for cancer immunotherapy but are hindered by preexisting immunity in humans, especially tobacco users at high risk for lung cancer. We show that barley stripe mosaic virus (BSMV) is relatively free of targeted antibodies in pooled human serum, warranting further development. We leverage cryo-electron microscopy and synthetic biology approaches to develop chemical and biological methods to functionalize the surface of BSMV virus-like particles (VLPs). We also demonstrate how these modular conjugation workflows enable multivalent targeting of immunomodulatory receptors and immune checkpoints. The functionalized particles are internalized by macrophages in vitro, leading to dose-dependent activation of a pro-inflammatory phenotype. Furthermore, we evaluate therapeutic efficacy of functionalized BSMV VLPs in a three-dimensional, multicellular NSCLC model. This proof-of-principle introduces BSMV VLPs as a modular nanoparticle platform for next-generation solid tumor immunotherapy.