ITOC 2026 | Targeting the tumor secretome to improve immunotherapy in cold tumors

Yeah, so of course we’ve seen great things coming off immunotherapy and in several different tumor types we see very profound responses. But the reality is also that there are a lot of tumors, actually the majority, that still do not respond to these therapies. And clearly there is a large need to also extend the success of immunotherapy to those tumors and one of the most powerful ways of a tumor to modulate its environment which includes its interaction with immune cells is by altering its communication and communication can happen through cell surface interactions or secreted factors. But it was a surprise to me that most of the immunotherapy field really has focused on these cell surface interactions, right? The PD-1, TIM3, LAG3, CTLA4, they’re all cell surface-bound factors. But what happens at the level of the secretome and how that impacts immunomodulation is still much more of a black box. So the challenge that we wanted to tackle is can we identify how cancers deregulate their secretome and how that associates with these tumor types that are traditionally considered cold. Now, one of the reasons why the secretome is so difficult to tackle is because these factors are usually quite lowly abundant proteins and they tend to get overshadowed by other very abundant proteins like albumin in traditional mass spec approaches. So we use a strategy in which we introduce an amino acid analog that gets incorporated into newly synthesized proteins. And this amino acid analog has a tag that allows you to pull it out selectively using beads. It’s a published method, not by us, called BioCAD, but we’ve applied this to these organoids, and it really allows us to selectively isolate the secreted factors. And we focused on colorectal cancer as a stereotypical tumor type that is cold and unresponsive. So what we’ve done is use organoids, so 3D cultures of tumor cells or of normal cells, to see how does the secretome diverge if you compare normal colon cells to this subtype called microsatellite stable colon cancer, which is very poorly responsive, microsatellite instable colon cancer which is very highly responsive to immunotherapy and we see very profound changes in the secretome, sometimes up to 25 to 30 percent of the entire secretome is altered when cells transition from normal to cancer and so we’ve looked into that and that really suggests that these cancers deregulate this axis of communication even without any perturbation from the microenvironment because these organoids were all cultured under identical conditions and then we overlaid this with data sets that showed tumor cells, tumors that were either strongly or poorly infiltrated by immune cells and looked which of the secreted factors that we now identify in our secretome analysis associate with those tumors that show an immune-excluded phenotype. And looking at four different data sets, we consistently found a key protein coming back there, and that protein is NOTUM, that’s a negative inhibitor of the Wnt pathway and that seems to in all of these data sets mark immune-excluded cancers so for us this is an important step because this is a technological step where we can now really reliably in that high depth profile the secretomes of these cancers and by integrating these patient-derived functional models with secretomes and clinical data sets we can start to triangulate factors that seem to associate with these cold tumors.

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