Unity World of Futanari!

World of Futanari is set in a dystopian future where drugs were created to control the population as the male population dwindled and the futa population grew. Originally marketed as pleasure enhancers, newer drug versions now strip away self-control and reduce people to primal, animalistic states open to demonic influence.

The drug company has its own agenda: break the futa population's will and unlock their supernatural abilities to create a submissive breed of superhumans. Hiro, one of the few surviving males in The Purifiers, has a rare resistance to the mutation and may be humanity's last hope. The 2D-game combat and 2DCG art carry the look.

Female domination, futa/trans, animated scenes, big-ass and big-tits design, drugs, and dystopian-setting framing all factor in. If you want a serious-tone futa dystopia with combat mechanics and a male protagonist resisting the spread, World of Futanari commits to that scope.