SharePoint Flex will work on any system/infrastructure that does not restrict the installation of Flex Web Parts and Template and is not bound by any other restriction that applies to the topology and rules of the shared environment in question.
In Private Cloud VPN environments there are no issues because the Administration of the virtual session would have no restrictions but this is not true in a completely shared situation/environment.
The problem is not with the SharePoint Flex product but with the restrictive nature and rules of a multi hosted environment such as Office 365.
Compatible environments for a Flex system must allow for the installation of third party web parts, some of which require access to the GAC. In addition, Flex needs to be installed via an import-web PowerShell script.
Furthermore, other Administration settings that control the features and capacity of Flex site such as the Threshold Throttle may need to be modified at some point so that cannot be restricted.
Flex is not compatible with Microsoft 365 as an app but can be utilized as part of a Hybrid solution.