Mathematical modeling of immune counter-regulation predicts efficacy of fractionated CD8+ T cell dosing strategies.

T cells (TSTs) induces tumor regression but rarely achieves durable responses in solid tumors. This limitation stems from secondary counter-regulatory mechanisms that are also induced by ACT, notably the recruitment of tumor-infiltrating myeloid cells (TIMs). However, the precise dynamics of these responses and the optimal TST dosing strategies to overcome their immunosuppression remain largely unclear. Here, we developed a mathematical model of ACT incorporating TIM-driven counter-regulation and simulated alternative TST dosing strategies based on data from B16F10 melanoma-bearing mice. Our models revealed that, compared with a single administration strategy, fractionated and response-guided dosing strategies reduced tumor burden by up to 83% while using about 40% fewer TSTs. These results were supported by transcriptomic analysis showing that ACT-induced TIMs initially exhibited pro-inflammatory traits but later shifted into suppressive states, suggesting that fractionated TST dosing could repeatedly induce their stimulatory potential. Together, our findings advance understanding of counter-regulatory mechanisms in ACT and highlight the potential of fractionated dosing as a rational strategy to overcome them.