Interferon-beta (IFN-β), an extracellular cytokine that initiates signaling pathways for gene regulation, has been demonstrated to function as a tumor suppressor protein through lentiviral gene transduction. In this article, I review the relevant previous works and propose a cell cycle-based, tumor suppressor protein-mediated mechanism of anti-cancer surveillance. IFN-β induces a tumor cell cycle alteration that leads to S phase accumulation, senescence entry, and a loss of tumorigenicity in solid tumor cells. IFN-β does not show a significant cell cycle effect in their normal counterparts. Retinoblastoma protein RB1, another tumor suppressor protein, tightly controls the cell cycle and differentiation of normal cells, preventing them from being significantly impacted by the IFN-β effect. The interplay between IFN-β and RB1 acts as a mechanism of cell cycle-based, tumor suppressor protein-mediated anti-cancer surveillance that can selectively suppress solid tumor or proliferating transformed cells from the loss of control leading to cancer. This mechanism has important implications for the treatment of solid tumors.