I recommend reading the article. It demonstrated that macrophages overexpressing Clever-1 (= stab1) no longer normally phagocytosed dying cancer cells, and therefore could not present their antigens to the immune system. In other words, they became those anti-inflammatory macrophages, which is a bad thing in a cancer tumor. The study also showed the mechanism by which this happens: α (SIRPα)-CD47 signaling actively prevents macrophages from eating cells. So, not just a lack of function, but active immunosuppression.
Then the researchers injected cancer cells into mice, which then formed a cancer tumor. After this, they directly injected Clever-1 overexpressing macrophages into the tumor and observed that the tumors grew much faster afterwards. The study then showed that this effect disappears when the α (SIRPα)-CD47 pathway is blocked, thus confirming the mechanism in vivo through that route as well.
But what is interesting here is the second part of the study, where mice were given cancer cells resistant to osimertinib (a biological cancer drug used to treat non-small cell lung cancer), which then started to form a tumor. Well, osimertinib did not help much with these tumors (which is not surprising). But when the researchers injected Clever-1-silenced macrophages (macrophages without Clever-1) into these tumors, the growth of the tumors slowed down significantly even without osimertinib, and even more so with it.
In other words, the study showed that a tumor that responded poorly to osimertinib and grew rapidly responded very well to a combination of Clever-1-silenced macrophages and osimertinib.
Why is this interesting when considering bex? Well, because bex specifically binds to those Clever-1 receptors and inhibits their function (cf. macrophages without Clever-1). And it is already known that bex can guide the immunological “type” of macrophages towards a pro-inflammatory direction in tumors (even when bex is administered systemically), so the effect should be biologically significant (because it does not compare to Clever-1-silenced macrophages). In any case, against this background, it can be assumed that pharmacological inhibition with bex can very well mimic the local Clever-1 silencing of macrophages and achieve a similar efficacy.
In addition, this highlights the role of macrophages in the tumor and shows that the Clever-1 status of macrophages locally in the tumor is sufficient for a therapeutic effect (and other systemic effects may not be necessary), because the study indeed injected those Clever-1 overexpressing or Clever-1 silenced macrophages directly into the cancer tumors.
This provides mechanistic evidence that Clever-1-positive macrophages are not just a biomarker, but an active mechanism promoting tumor growth and drug resistance (via the SIRPα–CD47 pathway). Then, locally Clever-1-inhibited macrophages restore normal phagocytosis and improve the efficacy of osimertinib, which supports the use of Clever-1 inhibition-based therapies, such as bex, in combination therapies. In other words, Clever-1 is NOT downstream where the problem is, but Clever-1 is precisely critical for the genesis of the problem upstream.