Metabolism-driven Immune Escape Defines Therapeutic Vulnerability in Type I and Type II Ovarian Cancer

Dualistic Classification of Ovarian Cancer and Immune Contexture

The dualistic model of ovarian cancer provides a foundational framework for understanding the biological heterogeneity of epithelial ovarian tumors (6, 7). This model categorizes ovarian cancer into Type I and Type II tumors based on histopathological appearance, molecular alterations, clinical behavior, and presumed cells of origin. Importantly, these distinctions extend beyond tumor classification and profoundly influence tumor–immune interactions and responsiveness to immunotherapy (7).

Type I ovarian cancers are typically low-grade and genetically stable tumors that arise through a multistep carcinogenic process (9, 10). Representative histological subtypes include endometriosis-associated ovarian cancer, ovarian clear cell carcinoma, endometrioid carcinoma, and low-grade serous carcinoma. These tumors frequently originate from well-defined precursor lesions, such as endometriosis or borderline tumors, and accumulate oncogenic alterations gradually over time (10). This stepwise evolution is accompanied by prolonged exposure to chronic inflammatory stimuli, oxidative stress, and immune surveillance (10).

The slow progression of Type I tumors allows sustained crosstalk between tumor cells and immune components within the tumor microenvironment. As a result, immune recognition is often incomplete rather than absent, giving rise to an immune contexture characterized by low-to-intermediate infiltration of cytotoxic T lymphocytes, macrophages, and other immune cell populations (11, 12). Although immunosuppressive mechanisms are active, immune exclusion is rarely absolute, suggesting that immune equilibrium or immune editing may occur during tumor evolution.

In contrast, Type II ovarian cancers, which are dominated by high-grade serous carcinoma, exhibit fundamentally different biological behavior. These tumors are highly aggressive, rapidly progressing, and genetically unstable, with near-universal TP53 mutations and frequent homologous recombination deficiency (9, 13). Current evidence strongly supports the distal fallopian tube epithelium as the primary site of origin for many Type II tumors, from which malignant cells disseminate early into the peritoneal cavity.

Because malignant transformation in Type II tumors occurs abruptly and dissemination follows swiftly, immune evasion mechanisms are established at early stages (14). These tumors frequently display defective antigen presentation, altered cytokine signaling, and profound immune exclusion, resulting in sparse infiltration of functional cytotoxic lymphocytes (5, 13, 14). Consequently, Type II tumors often bypass immune equilibrium and progress directly toward immune escape.

Taken together, the dualistic classification reflects not only differences in tumor genetics and histology but also distinct immune evolutionary trajectories. Recognizing these differences is essential for interpreting clinical trial outcomes and designing immunotherapeutic strategies tailored to ovarian cancer subtypes.

The key differences between Type I and Type II ovarian cancer, including tumor evolution, dominant metabolic pathways, immune contexture, and rational therapeutic strategies, are summarized in Table I.

Type I Ovarian Cancer: Glycolytic Metabolism and Modifiable Immune Suppression

Molecular determinants of glycolytic reprogramming. Type I ovarian cancers are characterized by recurrent alterations in genes involved in chromatin remodeling and intracellular signaling pathways, including ARID1A, PIK3CA, PTEN, and components of the MAPK cascade (10, 15, 16). Among these, loss of ARID1A is particularly significant, as it disrupts SWI/SNF chromatin remodeling complexes and alters global transcriptional regulation.

ARID1A deficiency has been associated with enhanced cellular plasticity, impaired DNA damage responses, and altered stress adaptation. Importantly, these changes extend to metabolic regulation, promoting transcriptional programs that favor glucose uptake and glycolytic flux (8, 16). In parallel, activation of PI3K/AKT/mTOR signaling enhances anabolic metabolism, protein synthesis, and nutrient acquisition, further reinforcing dependence on aerobic glycolysis (8).

The inflammatory microenvironment characteristic of endometriosis-associated tumors stabilizes hypoxia-inducible factors, particularly HIF-1α, even in the absence of severe hypoxia (10). HIF-1α directly upregulates glycolytic enzymes and glucose transporters, thereby amplifying glycolytic metabolism and lactate production (8, 16). Collectively, these molecular events establish a metabolic phenotype optimized for survival in inflammatory and hypoxic niches.

Glycolysis as a regulator of tumor immunity. The glycolytic phenotype of Type I ovarian cancer exerts multifaceted effects on antitumor immunity. Enhanced glucose consumption by tumor cells creates metabolic competition within the tumor microenvironment, depriving infiltrating immune cells of glucose required for activation, proliferation, and effector differentiation (17-19). Activated T cells are highly glycolysis-dependent, and glucose restriction directly compromises their cytotoxic capacity (17, 18).

In addition, lactate accumulation resulting from aerobic glycolysis leads to extracellular acidification, which suppresses T-cell receptor signaling, cytokine production, and migration (16-19). Acidic conditions also favor the polarization of macrophages toward immunosuppressive phenotypes, further dampening antitumor immune responses (19). These metabolic constraints collectively establish an immune-suppressive microenvironment.

However, unlike immune exclusion observed in Type II tumors, immune suppression in Type I ovarian cancer is often partial and spatially heterogeneous. Immune cells are present but functionally constrained rather than physically excluded (11, 14). This distinction has important therapeutic implications, as it suggests that metabolic barriers to immunity may be reversible.

Therapeutic implications and immunotherapy strategies. The presence of modifiable immune suppression in Type I ovarian cancer supports the rationale for combination immunotherapeutic strategies. Clinical trials of ICIs as monotherapy have demonstrated limited efficacy, underscoring the need for rational combinations informed by tumor biology (1-4, 20).

Targeting glycolytic pathways or upstream regulators such as PI3K/AKT/mTOR may alleviate metabolic stress on immune cells and enhance antitumor immunity (16, 21). In addition, epigenetic modulation associated with ARID1A loss may improve antigen presentation and immune recognition (15). The relative genetic stability of Type I tumors also favors the development of cancer vaccines targeting shared tumor antigens or recurrent neoantigens (18).

Adoptive cell therapies, including T-cell receptor (TCR)-engineered or chimeric antigen receptor (CAR)-modified T cells, represent another promising avenue, particularly when combined with strategies that improve immune cell infiltration and function (22, 23). Together, these approaches aim to transform a metabolically constrained but immunologically accessible tumor microenvironment into one permissive for durable immune-mediated tumor control.

Type II Ovarian Cancer: Lipid Metabolism and Metabolic Adaptation

Metabolic characteristics of type II ovarian cancer. Type II ovarian cancers, predominantly represented by high-grade serous carcinoma, exhibit metabolic programs that are fundamentally distinct from those of Type I tumors. Rather than relying primarily on aerobic glycolysis, Type II tumors display a pronounced dependence on lipid metabolism to sustain rapid proliferation, dissemination, and survival in hostile microenvironments (8, 21, 24).

This lipid-centric metabolic phenotype is closely linked to the anatomical and biological features of Type II ovarian cancer. Following early dissemination from the fallopian tube epithelium, tumor cells preferentially colonize the peritoneal cavity and omentum, environments that are rich in adipocytes and lipid substrates (9, 25, 26). This unique metastatic pattern provides selective pressure favoring tumor cells capable of exploiting exogenous lipids as major energy sources.

Fatty acid uptake and β-oxidation as energy sources. A defining feature of Type II ovarian cancer metabolism is enhanced uptake and utilization of fatty acids. Tumor cells upregulate fatty acid transporters and lipid-handling proteins, facilitating efficient acquisition of lipids released from surrounding adipocytes. Once internalized, fatty acids are directed toward mitochondrial β-oxidation, generating large amounts of ATP and reducing equivalents that support rapid cell growth and survival (27, 28).

Compared with glycolysis, fatty acid β-oxidation provides a highly efficient energy yield, which may be particularly advantageous in nutrient-variable environments such as the peritoneal cavity. This metabolic flexibility allows Type II tumor cells to thrive even under conditions of glucose limitation or hypoxia, conferring a survival advantage during dissemination and metastatic colonization (21, 24).

Adipocyte–tumor metabolic coupling in the peritoneal niche. The omentum and peritoneal fat pads serve not merely as passive sites of metastasis but as active metabolic partners for Type II ovarian cancer cells. Adipocytes in the tumor microenvironment undergo lipolysis in response to tumor-derived signals, releasing free fatty acids that are readily taken up by cancer cells (26).

This bidirectional metabolic crosstalk establishes a symbiotic relationship in which adipocytes supply energy substrates while tumor cells remodel the surrounding stroma to facilitate further lipid release (26, 29). Such metabolic coupling accelerates tumor growth, enhances invasiveness, and contributes to resistance against metabolic stress. Importantly, this interaction distinguishes Type II ovarian cancer from many other solid tumors and underscores the central role of lipid metabolism in its biology.

Lipid metabolism and cellular stress adaptation. Beyond energy production, lipid metabolism in Type II ovarian cancer plays a critical role in cellular stress adaptation. Fatty acid oxidation supports mitochondrial function, redox balance, and resistance to oxidative stress, all of which are essential for tumor cell survival during dissemination through the peritoneal cavity (27, 28).

Moreover, lipid-derived metabolites serve as signaling molecules that influence transcriptional programs associated with proliferation, invasion, and survival (21, 30). By integrating metabolic and signaling functions, lipid metabolism enables Type II tumor cells to maintain growth-promoting pathways even in the face of immune-mediated and therapeutic stress.

Implications for tumor progression and therapeutic resistance. The reliance of Type II ovarian cancer on lipid metabolism has significant implications for disease progression and treatment response. Lipid-driven metabolic programs support rapid tumor expansion, facilitate peritoneal dissemination, and contribute to resistance against conventional chemotherapy (24, 26). In addition, these programs create a metabolic landscape that is fundamentally distinct from that of Type I tumors, necessitating different therapeutic approaches.

Importantly, lipid metabolism does not operate in isolation but intersects with growth factor signaling, inflammatory pathways, and immune regulation (28, 31, 32). These interactions lay the groundwork for more complex survival mechanisms, including those mediated by heparin-binding epidermal growth factor-like growth factor (HB-EGF), which further reinforce tumor aggressiveness and immune evasion (33-37).

Transition to immune exclusion and advanced survival signaling. While lipid metabolism alone provides a substantial growth advantage, its full impact on disease progression becomes evident when coupled with downstream survival and immune-modulatory pathways. In Type II ovarian cancer, lipid metabolic adaptation creates a permissive environment for the activation of additional signaling networks that promote immune exclusion and therapeutic resistance (14, 22, 28).

Thus, lipid metabolism should be viewed as the metabolic foundation upon which more specialized survival mechanisms are constructed. Understanding this foundation is essential for interpreting the complex interplay between metabolism, growth factor signaling, and immune escape that characterizes advanced Type II ovarian cancer (24, 38, 39).

Type II Ovarian Cancer: HB-EGF Signaling and Immune Exclusion

HB-EGF as a downstream driver of aggressive tumor behavior. While lipid metabolic adaptation provides a fundamental survival advantage to Type II ovarian cancer cells, metabolic reprogramming alone does not fully explain the profound immune exclusion and therapeutic resistance observed in advanced disease (8, 21, 24). Accumulating evidence indicates that HB-EGF functions as a critical downstream mediator that translates metabolic fitness into sustained survival signaling and immune escape (33-37).

HB-EGF is a member of the epidermal growth factor family and is synthesized as a membrane-anchored precursor that undergoes proteolytic shedding to generate a soluble, biologically active form (33, 34). In Type II ovarian cancer, HB-EGF is markedly overexpressed in tumor tissues, ascites, and peritoneal dissemination sites (33-37). Both autocrine and paracrine HB-EGF signaling activate EGFR and related ErbB receptors, promoting cell survival, proliferation, adhesion, invasion, and angiogenesis (35, 36).

Importantly, HB-EGF expression is tightly linked to the biological context of Type II ovarian cancer, which is characterized by rapid dissemination, peritoneal fluid exposure, and metabolic stress (24, 26). Under these conditions, HB-EGF signaling provides a robust survival advantage, enabling tumor cells to withstand hostile microenvironmental pressures, including immune-mediated cytotoxicity (14, 20).

HB-EGF and peritoneal dissemination. Peritoneal dissemination represents a defining feature of Type II ovarian cancer and a major determinant of poor prognosis (6, 7). Tumor cells shed into the peritoneal cavity must survive in suspension, adhere to extracellular matrices, invade secondary sites, and establish metastatic colonies. HB-EGF plays a central role in each of these steps (33-37).

Experimental studies have demonstrated that HB-EGF enhances tumor cell survival in peritoneal fluid, promotes adhesion to mesothelial surfaces, and facilitates invasion through extracellular matrices (33-37). By activating EGFR-dependent signaling pathways, HB-EGF supports cytoskeletal remodeling, cell motility, and resistance to anoikis (33-37). These properties are particularly relevant in lipid-rich peritoneal environments, where metabolic adaptation and growth factor signaling cooperate to accelerate metastatic spread (26, 29).

Thus, HB-EGF functions not merely as a growth factor but as an orchestrator of peritoneal dissemination, integrating survival signaling with the unique anatomical and metabolic features of Type II ovarian cancer (36, 37).

HB-EGF as a modulator of the tumor immune microenvironment. Beyond its tumor-intrinsic effects, HB-EGF contributes to shaping an immunosuppressive and immune-excluded tumor microenvironment (5, 14). Persistent activation of HB-EGF–EGFR signaling promotes the production of cytokines, chemokines, and extracellular matrix components that alter immune cell recruitment and spatial distribution (14, 32).

In Type II ovarian cancer, immune cells are often retained at the tumor periphery rather than penetrating tumor nests, resulting in an immune-excluded phenotype (5, 11, 14). HB-EGF signaling is thought to reinforce this spatial segregation by modulating adhesion molecules and stromal architecture, thereby creating physical and biochemical barriers to immune infiltration (36, 37).

Furthermore, HB-EGF–mediated survival signaling enables tumor cells to resist immune-mediated stress, including cytotoxic T-cell attack and inflammatory cytokine exposure (20, 22). This resistance reduces the effectiveness of endogenous antitumor immunity and limits the clinical benefit of immune checkpoint blockade when administered as monotherapy (1-4, 20).

Therapeutic targeting of HB-EGF in Type II ovarian cancer. Given its central role in tumor survival, dissemination, and immune modulation, HB-EGF represents an attractive therapeutic target in Type II ovarian cancer (33-37). Unlike strategies that target EGFR broadly, inhibition of HB-EGF offers the potential to selectively disrupt a ligand-driven survival axis that is highly active in ovarian cancer (36, 37).

Preclinical and early clinical studies have demonstrated that targeting HB-EGF can suppress tumor growth, reduce peritoneal dissemination, and enhance chemosensitivity (33-37). By attenuating HB-EGF− dependent signaling, it may be possible to weaken tumor cell defenses and remodel the tumor microenvironment in a manner that restores immune accessibility (14, 37).

From an immunotherapeutic perspective, HB-EGF inhibition may function as a priming strategy that converts immune-excluded tumors into immune-accessible ones (5, 20). Combining HB-EGF–targeted therapy with ICIs, anti-angiogenic agents, or DNA damage–based therapies such as PARP inhibitors represents a rational approach for overcoming resistance in Type II ovarian cancer (3, 31, 32, 40, 41).

Integration of HB-EGF signaling into precision immunooncology. The integration of HB-EGF signaling into a broader metabolic–immune framework highlights its role as a subtype-specific vulnerability in Type II ovarian cancer (9, 24). Lipid metabolism establishes the metabolic foundation for aggressive tumor behavior, while HB-EGF signaling amplifies survival capacity and enforces immune exclusion (26, 36, 37).

This hierarchical model underscores the importance of targeting not only metabolic dependencies but also the downstream signaling pathways that convert metabolic fitness into immune resistance (21, 22, 42). In this context, HB-EGF emerges as a critical node linking metabolism, tumor progression, and immune escape (33-37).

Recognizing HB-EGF as a central mediator of immune exclusion provides a conceptual basis for precision immuno-oncology strategies tailored to Type II ovarian cancer. Such approaches prioritize restoration of immune access and sensitivity rather than reliance on immune checkpoint blockade alone (20, 36, 37, 43).

Therapeutic Development and Clinical Translation Based on Metabolic Subtypes of Ovarian Cancer

Accumulating insights into the metabolic heterogeneity of ovarian cancer have begun to influence therapeutic development and clinical trial design (8, 21, 24, 42). The recognition that Type I and Type II ovarian cancers rely on fundamentally distinct metabolic programs has provided a biological rationale for subtype-oriented treatment strategies rather than uniform therapeutic approaches (9, 24, 30). Representative metabolism-oriented therapeutic strategies and their stages of clinical development in Type I and Type II ovarian cancer are summarized in Table II.

In Type I ovarian cancer, which is characterized by glycolysis-dominant metabolism and stepwise tumor evolution, therapeutic efforts have focused on targeting glucose utilization, oncogenic signaling pathways linked to metabolic regulation, and epigenetic vulnerabilities associated with chromatin remodeling defects (9, 10, 16, 24). Inhibitors of the PI3K/AKT/mTOR pathway, HIF-related signaling, and metabolic enzymes involved in glycolysis have been explored in preclinical and early-phase clinical studies (16, 24, 42). Although these agents have shown limited efficacy as monotherapies, they are increasingly being evaluated in combination with ICIs, based on the concept that alleviating metabolic constraints may restore antitumor immune activity.

By contrast, therapeutic development for Type II ovarian cancer has largely centered on exploiting lipid metabolism, DNA damage repair defects, angiogenesis, and growth factor–dependent survival pathways (24, 26, 30, 32). High-grade serous carcinoma exhibits strong dependence on fatty acid metabolism and is supported by adipocyte-rich metastatic niches, providing a rationale for targeting lipid utilization and mitochondrial metabolism (26, 29, 39). In parallel, the success of PARP inhibitors in homologous recombination–deficient tumors has demonstrated the feasibility of biologically driven therapy in this subtype (40, 41). More recently, attention has turned to strategies that combine metabolic intervention, survival signaling blockade, and immunotherapy, including inhibition of HB-EGF–dependent pathways to overcome immune exclusion (31, 33-38, 42, 44).

Importantly, these subtype-specific therapeutic concepts are increasingly reflected in ongoing and planned clinical trials, highlighting a shift toward precision treatment based on tumor biology rather than histology alone (7, 20, 24, 30, 38, 45).

Future Perspectives

Future progress in ovarian cancer immunotherapy will depend on a deeper understanding of how tumor metabolism orchestrates immune escape and therapeutic vulnerability (5, 8, 21, 24, 42). The emerging distinction between glycolysis-dominant Type I tumors and lipid-dependent Type II tumors provides a conceptual framework for moving beyond empiric treatment strategies toward rational, biology-driven interventions (9, 24, 30).

For Type I ovarian cancer, future research should prioritize identifying metabolic and epigenetic modifiers that can convert immune-suppressive but infiltrated tumors into immune-responsive ones (10, 16, 18, 19). Integration of metabolic modulation with immune checkpoint blockade, cancer vaccines, and adoptive cell therapies represents a promising avenue (17, 20, 22, 23, 38). Advances in spatial transcriptomics and single-cell profiling will further clarify how metabolic gradients and immune cell function interact within the tumor microenvironment, enabling more precise patient selection and treatment timing.

In Type II ovarian cancer, the primary challenge lies in overcoming entrenched immune exclusion (5, 14, 20). Lipid metabolism, growth factor–dependent survival signaling, and stromal interactions cooperate to create a microenvironment that resists immune infiltration (26, 29, 31, 39). Therapeutic strategies that dismantle these barriers – such as targeting HB-EGF signaling, lipid utilization, angiogenesis, and DNA damage repair – are likely to be most effective when combined with immunotherapy (33-37, 40-42, 44, 46). Importantly, these approaches should be designed to restore immune access before or alongside immune activation (20, 23, 43).

Across both subtypes, a critical future direction will be the incorporation of metabolic biomarkers into clinical trial design (24, 27, 42). Biomarkers reflecting glycolytic activity, lipid utilization, or growth factor signaling may help identify patients most likely to benefit from specific combination therapies (21, 24, 30). In addition, careful consideration must be given to potential on-target effects of metabolic interventions on immune cells, underscoring the need for balanced therapeutic strategies (17, 22, 28).

Ultimately, translating metabolism-based immunotherapy concepts into clinical benefit will require close integration of basic science, translational research, and innovative clinical trial designs tailored to ovarian cancer biology (7, 24, 30, 38, 45).