My question’s on a very specific phenomenon which I‘m probably not understanding fully. In short, I‘ve read several articles about conditions that do induce necroptosis, and ones that don’t in the TNFR downstream. I already have very basic knowledge (I know that RIPK3 and pseudokinase MLKL are important, I’ve personally succeeded inducing necroptosis in macrophages by caspase 8 inhibition such as using Z-VAD or Z-IETD + Smac mimetics (e.g. SM-164) with TNF stimulation, and this cell death was rescued using either Nec-1 or Necrosulfonamide).

However, here starts my question: I have been reading papers and many papers mention that Smac mimetic treatment can induce TNF, which then necroptosis can be induced with just Smac mimetics and caspase 8 inhibiton (such as Z-VAD). My understanding is that the TNF from Smac mimetic treatment is sufficient for inducing TNF-mediated necroptosis. However, other papers or conditions suggest that adding recombinant TNF is absolutely necessary (which was actually the same with my case/conditions as well). I guess it will of course depend on the cell type, concentration of Smac mimetics and Z-VAD etc. but I want to confirm that

1) my understanding is correct about why Smac+Z-VAD alone is sufficient to induce necroptosis (initiated by TNF?)

2) if this is TNF-mediated (since papers I read show using neutralizing TNF antibodies or knocking out TNFR1 will stop necroptosis), WHY does this happen (what is the general idea of why and how is TNF induced by Smac mimetics? It will help if it’s specific as possible).