As early as the late Sengoku period, Hashirama Senju had learned the Sage Mode of Shikkotsu Forest.
Although the Senju Clan and the Uchiha Clan had been enemies at the time, given the friendship Hashirama Senju and Madara Uchiha had built since childhood, Hashirama had proactively offered to teach him Senjutsu.
Madara Uchiha had initially refused.
Only after personally experiencing the obvious boost Senjutsu gave to one's strength did he seek out Hashirama Senju again and haughtily say that he could give it a try.
But he truly had not expected that, despite being a peerless genius, he would be unable to learn Sage Mode!
Whether one could learn Senjutsu seemed to depend entirely on fate.
Hagoromo Ōtsutsuki could learn it, but Hamura Otsutsuki could not.
Likewise, Hashirama Senju could learn it, but Madara Uchiha could not.
Jiraiya could learn it, but Orochimaru could not.
This forced Orochimaru in the "original work" to develop the Cursed Seal, something that carried a certain risk of losing control but allowed most people's bodies to absorb natural energy and possess Senjutsu Chakra.
Of course, Orochimaru's Cursed Seal was based on Jūgo's cells, and Jūgo had not even been born yet.
In short, Madara Uchiha had been forced to give up on Sage Mode back then.
This was also one of the main reasons he lost more than he won in his many clashes with Hashirama Senju.
If Hashirama Senju's odds against Madara Uchiha had been fifty-fifty before he learned Senjutsu,
then after learning it, the odds became seventy-thirty, or even eighty-twenty.
Hashirama Senju in Sage Mode had defeated even Madara Uchiha with the Eternal Mangekyou Sharingan, even when he brought along the Nine-Tails.
The reason Madara Uchiha brought the Nine-Tails to the battle at the Valley of the End was to endure Hashirama