KRAS Inhibitors in Pancreas Cancer: Facts and Hopes about the Immunotherapy We Have All Been Waiting for.

Introduction
Pancreatic ductal adenocarcinoma (PDAC), with one of the worst 5-year survival rates of any tumor type, has proven recalcitrant to most treatment or prevention advances over the last 10–15 years. There has been limited progress in targeted therapy for PDAC (due to a paucity of druggable targets), and immune checkpoint blockade is well-known to be ineffective in nearly all patients1. Hence, the same combination chemotherapy regimens approved more than 10 years ago remain the backbone of treatment for patients with advanced PDAC2.
Change is now afoot, as the central driver of PDAC biology – the mutated KRAS oncoprotein – can now be effectively targeted with novel small molecules3,4. KRAS was among the first oncogenes to be identified in human cancer, and KRAS mutations are particularly prevalent in PDAC (>90% of patients), where they serve as the initiating genetic event. As a result, pancreatic cancers become “addicted” to KRAS oncogenic signaling, which supports tumor cell growth and survival. Following decades of unfruitful efforts, an assortment of small molecule inhibitors of KRAS is now under development; some are specific for a particular mutant form of the protein (e.g., KRAS G12C) while others inhibit all members of the RAS family, including the wild-type protein (“pan-RAS” inhibitors). Although two allele-specific inhibitors (adagrasib and sotorasib) have so far been FDA-approved for patients with lung and colorectal cancer, clinical use has been met with a pattern of therapeutic resistance (as is typical for targeted therapy) that is largely explained by the emergence of other mutated or amplified molecular pathways in the tumor cells that replace oncogenic KRAS signaling3.
In both preclinical and clinical studies, inhibiting KRAS in addicted cancer cells causes their rapid cell death and/or cell cycle arrest. In addition, there is now strong evidence that KRAS inhibition has anti-tumor effects that extend beyond the expected cell autonomous effects, resulting in a remodeled tumor immune microenvironment (TIME) and activation of the immune system5. Here, we summarize the increasingly understood connections between KRAS biology and tumor immunology and discuss the “facts and hopes” on how the convergence of tumor-intrinsic and -extrinsic signaling stands to transform the care of patients with PDAC (Figure 1).

FACTS

KRAS shapes the PDAC immune microenvironment
Three mammalian RAS genes (KRAS, HRAS, and NRAS) comprise the most frequently mutated oncogene family in human cancer. The RAS genes encode small guanosine-nucleotide-binding proteins that serve as critical intermediaries between extracellular signals and cellular functions such as proliferation, differentiation, migration, and survival6. In the (active) GTP-bound state, RAS proteins interact with effector proteins to initiate downstream signals (e.g., MAP kinase and PI3 kinase). RAS molecules possess an intrinsic GTPase activity that hydrolyzes GTP to GDP, thereby switching them from an active state to an inactive state. Most oncogenic RAS mutations perturb this GTPase activity, leading to persistent signaling. RAS proteins have been reported to have functions in virtually all tissues; in mice, Kras (but not Nras or Hras) is required for embryonic development, especially for the development of blood lineages7.
A defining manifestation of RAS signaling is cell proliferation, the result of enhanced activity of several cell-cycle regulators, including MYC4,6. Consequently, the pursuit of targeted anti-cancer therapies – from inhibitors of the ABL, EGFR, and RAF kinases to the more recent advent of direct RAS inhibitors – was grounded on their anti-proliferative potential. However, there is an increased understanding that cell cycle programs within tumor cells are closely linked to the makeup of the surrounding TIME8. One of the first examples of this relationship came from studies in melanoma, for which tumor-intrinsic signaling by beta catenin, a critical component of the Wnt signaling pathway, suppresses T cell infiltration, leading to immune checkpoint blockade (ICB) resistance9. Similar findings have been reported for CDK4/6 inhibitors in breast cancer10 and lung cancer11, while our own work in PDAC revealed that CDKN2A/B deletions and MYC amplifications are among the strongest predictors of a T cell low “cold” tumor12. The molecular mechanism(s) underlying this relationship remain unknown, with de-repression of endogenous retroviruses and the senescence-activated secretory response (SASP) among the possible explanations.
Given these findings, it is perhaps not surprising that inhibiting RAS signaling might have corresponding effects on immune infiltration13. Indeed, several candidate mediators of immunosuppression are downstream of KRAS in PDAC. Interleukin 8 (CXCL8), a neutrophil chemotactic factor that is upregulated in PDAC, was among the first immune-related chemokines to be linked to RAS signaling14. CXCL8 is one of several ligands for the C-X-C motif chemokine receptor 2 (CXCR2) – a ligand family that also includes CXCL1, CXCL2, CXCL3, and CXCL5. One or more of these chemokines are expressed to varying degrees across RAS-driven tumors15, and impeding CXCR2 signaling can block metastasis and sensitize tumors to ICB in preclinical models of PDAC16. Clinical evaluation of CXCR2 antagonists for cancer, infectious disease, and autoimmunity is ongoing17.
Granulocyte-macrophage colony-stimulating factor (GM-CSF), also known as colony-stimulating factor 2 (CSF2), is another target of KRAS signaling with profound immune effects. Transduction of primary pancreatic ductal cells with mutant KrasG12D prompted a 10–15-fold induction of GM-CSF in vitro and a marked infiltration of immunosuppressive Gr1+CD11b+ myeloid cells in vivo18. Importantly, suppressing GM-CSF blocks the infiltration of myeloid suppressive cells and results in a CD8 T cell-dependent inhibition of PDAC tumor growth18,19. It remains unclear how these findings might be leveraged for clinical benefit given that GM-CSF-containing vaccines given to patients with resectable PDAC seems to promote, rather than diminish, T cell infiltration20.
An interesting example of how mutant KRAS modulates the makeup and activity of the TIME comes from studies of the cytokine interleukin 17 (IL-17) and its receptor (IL-17RA)21. Whereas IL-17RA is expressed at low levels in normal pancreatic epithelial cells, its expression increases in premalignant pancreatic intraepithelial neoplasias (PanINs) and metaplastic cells following the induction of mutant KRAS. In parallel, KRAS signaling in the epithelium drives the secretion of IL-17 by immune cells by mechanisms unknown. The resulting KRAS-induced IL-17/IL-17RA crosstalk promotes inflammation to further accelerate neoplastic progression22.
The molecular details by which signals from mutant KRAS in cancer cells prompt the transcriptional changes which ultimately lead to an altered TIME landscape have yet to be worked out. Moreover, other factors downstream of mutant KRAS – including VEGFA, IL-6, IL-1b, TGFb, COX2, NFkB targets, PI3-kinase, and others – are likely to contribute to the reshaping of the TIME23. These findings strongly support the notion that PDAC cancer cells serve as a signaling hub, or “organizer,” of their surrounding microenvironments, with KRAS serving as a central coordinator of the changes23–25.
Based on these observations, one attractive paradigm has emerged: tumor-intrinsic KRAS signaling elaborates chemokines that drive attraction of immunosuppressive cells, especially myeloid cells, that then block T cell infiltration and activity26. The opportunity to block KRAS signaling might therefore blunt myeloid cells in the TIME and allow T cells to infiltrate. Moreover, because KRAS is the earliest oncogenic events in many cancers, KRAS’ orchestration of an immunosuppressive microenvironment also occurs early, evident even before invasion27. This suggests that KRAS signaling, and its immunosuppressive program, prevents an anti-tumor immune response from the earliest stages of malignant progression. We have previously argued that such primary immunosuppression represents a pathophysiology in which “immunoediting” is not operative because there is an insufficient adaptive immune response to drive Darwinian-like escape28. We hypothesized instead that therapeutically blocking KRAS signaling in tumor cells, were it to become possible, might jump start an immune priming response to a tumor that that had previously evaded notice by the immune system29. Nevertheless, RAS inhibition is likely to modulate the TIME through multiple mechanisms, including effects on cancer-associated fibroblasts, vasculature, and direct effects on T cells (Figure 2).

Pharmacologic KRAS inhibitors
Small molecule inhibitors of RAS became widely available after 2018 and the number and type of formulations has increasingly grown30. The first direct demonstration of the immune effects of blocking KRAS came several years earlier from genetic models of PDAC. To study the potential consequences of KRAS inhibition – at a time when the oncoprotein was still considered “undruggable” – two groups used genetic engineering to develop transgenic models in which mutant KRAS could be induced or de-induced by the addition or removal of doxycycline (“iKRAS” models). In both models, tumors that arise following induction of mutant Kras undergo regression when the oncogene is de-induced, establishing that Kras-mutant PDACs are “addicted” to continued signals from the oncoprotein31,32. Associated with these cell autonomous changes in tumor cells, Kras silencing reshapes the TIME33–36, demonstrating a direct link between cancer cell autonomous KRAS signaling and non-cell autonomous effects on the stroma.
These findings with genetic models have now been confirmed with small molecule KRAS inhibitors in the setting of pancreas cancer37–39 and lung cancer5,40. Although changes to the TIME exhibit some model-dependent differences, common features include a decrease in the abundance of immunosuppressive myeloid cells and an increase in lymphoid populations, including enhanced proliferation and cytotoxicity of T cells37,38,41. Importantly, these studies used allele-specific KRAS inhibitors whose activity is predicted to be limited to cancer cells, thus indicating that the effects on the microenvironment are indirect.
Adding to the repertoire of KRAS inhibitors, molecules with a broader specificity than these allele-specific drugs are being developed3,5,42–45. One such molecule, the RAS(ON) multi-selective inhibitor daraxonrasib (formerly known as RMC-6236), has activity against all RAS paralogs – KRAS, HRAS, and NRAS – and has shown promising clinical results in PDAC patients with metastatic disease treated in the second line of therapy46. In preclinical studies, a closely related RAS(ON) multi-selective inhibitor (RMC-7977) has strong anti-tumor effects and promotes similar changes in the TIME43,47, including increased infiltration of cytotoxic T cells. Interestingly, the addition of CDK4/6 inhibitors to RMC-7977 potentiates these effects on the TIME48. Similar effects on the TIME have been observed with the pan-RAS inhibitor ADT-100445 and KRAS degraders49, as well as following indirect targeting of the RAS pathway (e.g., combining an inhibitor of the RAS guanine exchange factor SOS1 with a MEK inhibitor)50.

KRAS inhibitors act in partnership with the immune system
Consistent with immune changes in the TIME following interruption of oncogenic KRAS signaling, there is increasing evidence that T cells and immune priming play a role in mediating the full anti-tumor effects observed with RAS inhibitors. When mice bearing mutant KRAS PDAC tumors are pharmacologically depleted of T cells at the time of treatment with RAS inhibitors, tumor regressions are not as deep or durable as in T cell replete mice, a finding observed for both KRAS G12D and RAS(ON) multi-selective inhibitors38,47. Both inhibitors, even as single agents, achieve a significant percentage of complete remissions in established KRAS-driven tumors, whereas CRs are not observed in T cell depleted mice. Upon discontinuation of RAS inhibition, tumors regrow faster in T cell depleted versus T cell replete mice.
This pattern of T cell dependency has been reported in multiple versions of the KPC (Kras; p53; Cre) pancreatic model (subcutaneous, orthotopic, and spontaneous) and for both MRTX1133 (KRAS G12D inhibitor) and RMC-7977 (RAS(ON) multi-selective inhibitor). Similar T cell dependency has been reported for KRAS G12C inhibitors and in lung and other mouse cancer models40,51,52. However, results vary from cell line to cell line, with more efficacy in tumors that are highly antigenic, feature significant T cell infiltration, or both. A good example is RMC-7977, which triggers robust regression in “T cell high” implanted KPC tumors but is less effective against “T cell low” KPC tumors, despite each tumor expressing mutant KRAS G12D47.
For RMC-7977, we further tested whether anti-tumor effects were dependent on dendritic cells (DC) that are considered necessary for priming T cells. In experiments utilizing BATF3 KO mice that lack antigen cross-presenting DC that mediate T cell priming, a blunted therapeutic response to RAS inhibition and a higher rate of relapse is observed compared to the same treatment in wild-type mice47. Two hypothesizes are raised by these observations: (i) KRAS inhibition alleviates oncogene-driven immunosuppression in the TIME, allowing effector T cells to contribute immediately to the anti-tumor effect; and/or (ii) tumor antigen released upon tumor cell death can be picked up by host DCs, which then prime tumor-specific T cells and establish immune memory.
Because therapeutic RAS inhibition mobilizes T cell immune responses, it was anticipated that RAS inhibitors would cooperate in PDAC models with immune checkpoint and immune agonists synergistically, as had been observed with KRAS G12C inhibitors across multiple models40,53. This hypothesis has been extensively tested in mouse PDAC models using combinations with anti-PD1 and other immune agents. Although PD-1 inhibitors fail to demonstrate reliable anti-tumor effects as single agents in PDAC mouse models, the combination of PD-1 and RAS inhibition is more effective than RAS inhibition alone47. Blockade of the immune checkpoint CTLA-4 can also synergize with RAS inhibitors for therapeutic effect, especially in combination with anti-PD-1. Evidence exists that the CTLA-4 effect is accomplished not only by blocking CTLA-4 from binding and inhibiting CD28 but also by depleting CTLA-expressing regulatory T cells (bioRxiv 2025.02.28.640711).
We and others have found additional synergy by adding immune agonists to varying types of RAS inhibition and ICB47,48,54. For example, the TNF superfamily receptor CD40, a non-ICB cell surface molecule whose ligation can activate and “re-educate” DC, B cells, and macrophages, cooperates with RMC-7977 plus ICB to increase the rate of complete remissions in certain mouse models, and has potent effects with RMC-7977 even without anti-PD-1 and anti-CTLA-447. Another study showed efficacy with the combination of MRTX1133, a CXCR1/2 inhibitor, blocking LAG-3 antibody, and importantly agonistic anti-41BB antibody, another member of the TNF superfamily of receptors54.
Most impressive has been the rate of complete remission and cures observed with RAS inhibitors plus immunotherapy combinations, that in some experiments persist even after RAS inhibition is discontinued. It remains to be understood whether the main immune mechanism of RAS inhibition plus immunotherapy is boosting pre-existing T cells, priming new T cells, both, or other. Although it is tempting to speculate that mutant KRAS itself serves as one of the antigen targets for this T cell response, evidence in mouse models has not been forthcoming. The situation in patients may be different because peptides derived from KRAS clearly bind to common MHC alleles on tumor cells, and a reactive T cell receptor repertoire in humans has been identified and functionally validated (leading to several potential KRAS TCR immunotherapies). Moreover, it is possible that the immunogenicity of mutant RAS peptides may be further increased by covalent KRAS inhibitors, due to their ability to generate haptenated drug-peptide conjugates that can bind MHC55–58. These concepts are nicely explored in a previous Facts and Hopes and elsewhere25,59–61.
The synergistic effects of RAS inhibition and immunotherapy agents are not universally observed across mutant KRAS mouse models, and one predictor appears to be the extent of pre-existing T cell infiltration. Accordingly, RMC-7977 in combination with ICB or ICB plus CD40 agonist is more effective in T cell high (“hot”) PDAC tumor clones than T cell low (“cold”)47, a finding that may inform the design of future immunotherapy trials.

A RAS inhibitor paradox for T cells
RAS signaling through the MAP kinase pathway plays a critical role in the activation and function of T cells and other immune cells62–66. These findings raise a paradox: how can the full effects of RAS inhibitors depend on engaging T cell responses if T cells use RAS for activation? Although this dilemma is probably not applicable in experiments using allele specific inhibitors that spare wild-type RAS activity in T cells, pan-RAS or multi-selective inhibitors can block wild type RAS, including NRAS, which may be the most functionally important RAS family member in T cells67. Importantly, the concentration of RMC-7977 needed to inhibit MAP kinase activity in T cells is much higher than the dose required to inhibit MAP kinase in tumor cells, suggesting a therapeutic window47. Nevertheless, non-tumor bearing mice respond in vivo to antigen-specific vaccination as well or perhaps better if treated with RMC-7977 vs. vehicle44,47. These results indicate that in vivo, administration of RAS multi-selective inhibitors at therapeutic doses is not systemically immunosuppressive. It is also possible that RAS inhibitors may block RAS activation in immunosuppressive or exhausted immune cells, leading to a net effect of immune stimulation rather than suppression. Mechanistic studies to explore these possibilities are required.
Other immune combinations with RAS inhibitors beyond ICB could be considered, including tumor vaccines, bispecific T cell engagers, or adoptive T cell therapy – again assuming the inhibitors do not themselves inhibit T cells that rely on RAS signaling. Combinations of RAS inhibition and chemotherapy, which are already being pursued in clinical trials, could also be synergistic in terms of immune response. Certain chemotherapies are considered to be immunogenic, at least in mouse models68, but it is also well-appreciated that for patients, ongoing chemotherapy is usually immunosuppressive, more so if given with steroids to prevent nausea and vomiting, as is customary69. In mouse models, nab-paclitaxel and gemcitabine chemotherapy – acting in part as a ‘vaccine’ to release antigen – synergize with ICB and CD40 antibodies in the KPC pancreatic model in a T cell- and DC-dependent fashion70,71. Adding RAS inhibitors to immunochemotherapy combinations could further promote this effect but remains to be tested. Dose and schedule of these agents will be important to optimize.

HOPES

KRAS inhibition may allow potent new ways to treat patients with pancreatic cancer
As of early 2025, more than 40 RAS inhibitors were under clinical investigation, a number that has certainly increased since then30. The hope is that RAS inhibition combined with immunotherapy will provide deeper and more durable clinical remissions in patients with PDAC in whom response to RAS inhibitors is otherwise short-lived and response to checkpoint inhibition is non-existent. Similar preclinical data with KRAS G12C inhibitors and PD-1 blockade led to a similar hope for patients with lung cancer. However, the first clinical trials testing this hypothesis were challenging due to toxicity that is reminiscent of failed attempts to combine BRAF inhibitors with ICB in patients with melanoma, despite preclinical data suggesting an opportunity72. These first results in patients with lung cancer, unfortunately, seem to have driven a prevailing view that RAS inhibition and immuno-oncology (IO) combinations are “too toxic”. However, more recent trials using other RAS inhibitors have shown much less toxicity and promising clinical results, reopening hope for such combinations in both lung cancer and pancreatic cancer. We feel it is important to understand carefully current and past attempts to combine KRAS G12C or BRAF inhibitors with anti-PD1/PDL1, but equally important not to assume that G12D or RAS(ON) inhibitors will have the same profile.
Clinical trials have already launched in PDAC with daraxonrasib and chemotherapy and/or cetuximab, so adding a PD-1 or PD-L1 inhibitor in the next cohort could be straightforward. If daraxonrasib is approved for patients with second-line metastatic PDAC, adding PD-1 or PD-L1 antibody in that clinical setting would be even more straightforward, although extensive first-line chemotherapy might leave patients deeply immunosuppressed and unlikely to mobilize an anti-tumor immune response. Preclinical data also supports the notion of adding anti-CTLA-4 to RAS inhibitor/immunotherapy combinations37. Although anti-CTLA-4 can potentially add toxicity, certain treatment designs such as lower-than-label doses of anti-CTLA-4, longer intervals between doses, and limiting CTLA-4 treatment to one or two doses have been useful in other IO combinations in patients with PDAC73.
If toxicity of combination therapy is too significant for most patients, sequential administration of a RAS inhibitor followed by immunotherapy (or vice versa) is worthy of exploring. RAS inhibitors and IO combinations could also be deployed in the maintenance setting for patients with advanced disease (i.e., in patients with unresectable disease who achieve clinical remission with chemotherapy which is then discontinued). We have previously outlined the argument for maintenance therapy after induction chemotherapy (instead of continuous chemotherapy) in patients with newly diagnosed, metastatic PDAC74, and clinical trials with this type of design have been promising75–77.
Because preclinically, both allele-specific KRAS inhibitors and RAS(ON) multi-selective inhibitors cooperate with immunotherapy, the choice of RAS inhibitor – and choice of PD-1/PD-L1 antibody or other ICB agent for the matter – remains empiric. Allele specific inhibitors spare RAS inhibition in T cells and other normal cells, but only a fraction of PDAC patients express any given mutation (e.g., KRASG12D is found in 35% of PDAC cases). Pan RAS inhibitors may be advantageous to block emergence of resistance to other KRAS mutations, but the full toxicity of also blocking wild type RAS, particularly in the setting of ICB, remains to be carefully determined. Another emerging option may be PROTACs to degrade the KRAS or RAS oncoprotein, including those that can be designed to affect only the mutated form and not wild type. Because degradation might deliver RAS species to the proteosome, it is hypothesized (and remains to be proven) that RAS degraders could increase antigen presentation of mutated RAS peptide-MHC complexes to trigger tumor-specific T cells. As RAS inhibition boosts the expression of class I MHC on tumor cells38,47, this could further augment presentation of RAS or other immunogenic peptides.
An important caveat from the preclinical studies, as noted above, is that RAS inhibitors and immunotherapy combinations work best, and sometimes only, in tumors with strong tumor-rejection antigens or tumors with high pre-existing T cell infiltration. This might suggest the need to pre-select patients based on antigenic inspection of the tumors (e.g., high neo-antigen load by DNA sequencing) or immune features in the TIME (high CD3+ T cells by IHC). Another caveat is that inclusion of immune agonists such as CD40 and 41BB antibodies in addition to ICB might be required in diseases such as PDAC, as suggested by preclinical studies47,48,54. Ultimately, agonists may need to be included to capture the full immune therapeutic potential of RAS inhibition. Hence, studies of RAS inhibitors and PD-1/PD-L1 that do not immediately demonstrate additive or synergistic benefit should not dissuade the field from pursuing the combination of RAS inhibition and IO.

KRAS inhibition could have power in patients beyond advanced disease
It is further hoped that relatively low toxicity from RAS inhibitors, which has thus far been manageable in patients with advanced PDAC, will enable the use of RAS inhibitors with immunotherapy beyond patients with advanced cancer. Post-surgical or adjuvant therapy with RAS inhibitors and IO in patients with resectable stage I-III PDAC – treated with or without chemotherapy – could hold great promise. The use of such combinations in a neoadjuvant (pre-surgical) scenario might be even more powerful, given the exciting results and unprecedented impact of ICB in the neoadjuvant setting for patients with local disease across multiple cancer types, especially melanoma and lung cancer78. Finally, RAS inhibitors with or without immunotherapy could also be tested in otherwise healthy individuals at high risk for developing cancer (such as BRCA1/2 germline mutation carriers) to “intercept” and otherwise clear pre-malignant pancreatic epithelial lesions, which are known to be of high prevalence and nearly always express mutant KRAS79–81.

Limitations
The promise of deploying KRAS inhibitors for patients with pancreatic cancer is tempered by the long list of prior therapeutic strategies in this disease that have ultimately not delivered in the clinic on initial excitement. Although compelling data have been produced using the KPC model, there are major differences between this model and humans with PDAC, not least of which is the embryonic engineered expression of mutant KRAS in the mice. Moreover, the immune effects with KRAS inhibitions have the most pronounced effects in tumors with at least moderate baseline T cell infiltrations, which is unlikely the case for the majority of patients with PDAC. Clinically, none of the inhibitors are as yet FDA approved for patients with pancreatic cancer. The full impact of toxicities such as rash, diarrhea, and fatigue – particularly in the earlier clinical setting – remains unknown, as is the toxicity in patients upon combining inhibitors with immune and other therapy. The formidable toxicity of checkpoint blockade with BRAF inhibitors in patients with melanoma is a stark reminder of what can happen when moving from mouse models to clinical trials82.

CONCLUSION
Inhibitors of oncogenic RAS may be the “immunotherapy” we have long been waiting for. For patients with PDAC, this hope is based on the successful and rapid clinical advancement of novel RAS inhibitors and ever-increasing preclinical data showing that RAS inhibition favorably modulates the TIME by reversing the numerous immunosuppressive features driven by oncogenic RAS signaling. Moreover, rapid death of oncogene-addicted tumors cells with a modality that is not itself immunosuppressive may permit a vaccine or immunizing effect in the patients. Thus, as we hypothesize here, therapeutic oncogenic RAS inhibition sets the stage for triggering or promoting T cell adaptive responses and establishing T cell memory that may be pharmacologically enhanced with standard and novel immunotherapies. If opportunistically developed in the clinic with immune insights in mind, RAS inhibitors are poised to be key components of novel combination therapy in PDAC to create deep therapeutic responses, address pharmacological resistance, and extend response durability and quality of life.