The binding of bevacizumab to circulating VEGF-A competitively inhibits VEGF-A binding to its endothelial cell surface receptors, ultimately inhibiting abnormal tumor angiogenesis (Figure 2). The 2022 NCCN guidelines recommended the simultaneous addition of bevacizumab to chemotherapy regimens for first-line treatment of OC, platinum-sensitive relapse, and second-line treatment of platinum-resistant relapse and, if effective, bevacizumab maintenance therapy at the end of chemotherapy (Armstrong et al., 2022). Two classic phase III clinical trials, ICON7 and GOG-0218 (Table 1), provided evidence that the addition of bevacizumab to standard first-line chemotherapy for EOC significantly improves PFS, and patients with poor prognosis, such as those with tumors with a high KELIM score and poor chemotherapy sensitivity, can benefit in terms of OS (Burger et al., 2011; Perren et al., 2011). Furthermore, in GOG-218, the analysis of many tumor biomarkers showed a positive correlation between OS and PFS and the efficacy of bevacizumab in first-line chemotherapy as high microvessel density (above the median) increased; similarly, high expression of tVEGF-a was positively associated with prolonged OS (Bais et al., 2017). These findings suggest that in future studies, we could consider microvessel density and tVEGF-a as potential biomarkers to predict the response to first-line treatment with bevacizumab and that specific subgroups of patients with high levels of these biomarkers would be more likely to benefit from first-line treatment including bevacizumab (Bais et al., 2017). Furthermore, in the second-line treatment of patients with platinum-sensitive recurrent OC (PSROC), the OCEANS trial (Table 1) showed that for patients not previously treated with bevacizumab, the mPFS was prolonged by 4 months with the addition of bevacizumab to the carboplatin and gemcitabine (GC) regimen compared to with the GC regimen alone (12.4 months vs 8.4 months), and the efficacy rate (79% vs 57%) indicated that the bevacizumab combination was more effective than the GC regimen alone (Aghajanian et al., 2012). Another trial (NCT01802749) found that bevacizumab remained effective when reintroduced in second-line therapy, with a 3-month prolongation of the mPFS (11.8 months vs 8.8 months). Combining the findings of these two studies, it can be concluded that patients with platinum-sensitive OC benefit from the use of bevacizumab in combination with chemotherapy in second-line therapy regardless of whether bevacizumab is used first and that the amplification of resistant clones may not lead to bevacizumab resistance (Pignata et al., 2021). Furthermore, in the GOG-0213 trial, the mPFS (13.8 months vs 10.4 months) and OS (42.2 months vs 37.3 months) were longer with the paclitaxel and carboplatin (PC) regimen plus bevacizumab than with the PC regimen alone; the effectiveness (78% vs 59%) suggests that the advantage of combining bevacizumab (Coleman et al., 2017). Second, in patients with platinum-resistant OC, AURELIA (Table 1) showed that bevacizumab combined with standard monotherapy was also effective in prolonging PFS (3.4 months vs 6.7 months) and the objective response rate ORR (11.8% vs 27.3%, p < 0.01) (Pujade-Lauraine et al., 2014). Intriguingly, a subgroup of patients with malignant ascites was distinguished in the AURELIA trial, and the addition of bevacizumab to chemotherapy was also found to improve ascites control (Pujade-Lauraine et al., 2014). In a GOG-218 subgroup analysis, PFS and OS were prolonged in patients with ascites on bevacizumab, although it was not directly reported whether bevacizumab had a direct effect on ascites control (Ferriss et al., 2015). A phase II clinical trial, REZOLVE, demonstrated the potential of intraperitoneal injection of bevacizumab (IP-bev) in delaying malignant ascites formation in chemotherapy-resistant EOC, and we expect more studies to demonstrate that similar palliative therapies can benefit patients with advanced OC with peritoneal metastases (Sjoquist et al., 2021). In Table 1, we summarize a portion of the phase III clinical trials of bevacizumab for OC to date.

Apatinib is a new generation oral tyrosine kinase inhibitor that highly selectively targets the VEGFR2 signaling pathway, primarily blocking VEGFR-induced endothelial cell migration and proliferation and reducing tumor microvessel density (Tian et al., 2011). A phase II prospective clinical study evaluated the efficacy and safety of apatinib monotherapy in 28 patients with recurrent platinum-resistant EOC, showing an ORR and disease control rate (DCR) of 41.4% and 68.9%, respectively; a mPFS and OS of 5.1 and 14.5 months, respectively; manageable toxicity; and good patient tolerance (Miao et al., 2018). This trial provided evidence that apatinib monotherapy is effective in patients with relapsed/platinum-resistant OC. In addition, the results from several clinical trials have shown that combination therapy with apatinib is beneficial and well tolerated by patients, although fistulas may occur (Teo et al., 2015). Unlike the single-arm phase II trial AEROC (NCT02867956), APPROVE (NCT04348032) enrolled more patients (152) and added a monotherapy arm with the chemotherapeutic agent pegylated liposomal doxorubicin (PLD) (Lan et al., 2018; Wang et al., 2022). In the comparison of PLD alone and PLD in combination with apatinib, the results showed that the median OS was prolonged by 2.5 months and 8.6 months, respectively, with a favorable safety profile. This study initially showed that combining apatinib with PLD in second-line chemotherapy in patients with platinum-resistant recurrent ovarian cancer (PROC) was more effective than PLD alone (Wang et al., 2014). Wang et al. conducted a small retrospective study in which they collected and analyzed clinical data from 41 patients who relapsed after receiving apatinib monotherapy or apatinib in combination with chemotherapy, and they found that apatinib delayed progression in OC patients with biochemical relapse (defined as only CA-125 increased by more than twice the normal value, usually 2–6 months earlier than clinical evidence, such as imaging presentation. (Wang et al., 2022). We look forward to further validating this result with a large-scale trial. Furthermore, a study identified profibronectin-1 (FBN1) as a key target of chemoresistance in OC by constructing an OC-like organ model. FBN1 regulates glycolysis and angiogenesis via VEGFR2/STAT2, and its inhibition reduced sensitivity to cisplatin in this model, providing evidence for the combination of an FBN1 inhibitor and apatinib for the treatment of platinum-resistant OC (Wang et al., 2022b). Yang et al. demonstrated that in vivo, PD-L1 binds directly to VEGFR2, induces tumor angiogenesis, and relies on the c-JUN/PD-L1/VEGFR2 signaling axis to participate in the progression, invasion, and metastasis of OC, which provides evidence for the use of the pD-L1 inhibitor durvalumab combined with the VEGFR2 inhibitor anlotinib to improve the OC therapeutic effect (Yang et al., 2021a). Based on previous studies, angiogenesis inhibitor-induced hypoxia induces HRDs by affecting homologous recombination repair (HRR)-related BRCA1, BRCA2, and RAD51, resulting in enhanced effects of PARPis (Figure 2) (Mittica et al., 2018; Ashton and Bristow, 2020). Furthermore, PARP1 inhibition impedes HIF1α accumulation and attenuates HIF1α-mediated anti-angiogenic drug resistance (Martí et al., 2021; An et al., 2021), and the PARP1 inhibitor fluzoparib in combination with anlotinib contributes to treatment efficacy (Wang et al., 2019a). We expect the results of relevant clinical experiments to provide meaningful guidance for the treatment of OC.

Anlotinib is a new oral multitarget tyrosine kinase inhibitor. Anlotinib selectively targets VEGFR2/3 and fibroblast growth factor receptor (FGFR) one to four with high affinity to inhibit VEGF/VEGFR signal transduction and platelet-derived growth factor receptor α and β as well as the activity of stem cell factor receptor (c-Kit) and Ret (Sun et al., 2016). Many studies have shown that anlotinib has a good therapeutic effect in patients with platinum-resistant and refractory OC. For example, a retrospective study in 2020 showed the benefits of single-drug treatment with anlotinib; although the number of patients included in this study was small, the DCR was 85.7%, suggesting that anlotinib had good application prospects (Ni et al., 2020). Therefore, large-scale clinical prospective and retrospective studies are needed for further verification. Su et al. found that anlotinib reactivates the immune microenvironment and relies on CD4⁺ T-cell to promote the normalization of tumor blood vessels; therefore, the combination of anlotinib and ICIs can enhance treatment efficacy (Su et al., 2022). A small retrospective study involving 32 patients with advanced EOC who had received at least two existing standard treatments showed that the efficacy of anlotinib combined with a PD-1 blocker in the treatment of advanced EOC was good, with a mPFS of 6.8 months and a median OS of 18.5 months (Li et al., 2022c). Lan et al. found that the objective effective rate of erlotinib combined with the PDL1 inhibitor TQB2450 was 47.1%, the DCR was 97.1%, and the mPFS was 7.8 months, showing promising antitumor activity and controllable toxicity (Lan et al., 2022). In patients with platinum-resistant or refractory OC, a phase Ib study of the injection of the PD-L1 inhibitor TQB2450 in combination with anlotinib has preliminarily demonstrated an antitumor effect, with a duration of remission (DOR) reaching 97.1% and a DOR of more than 8 months in 61.3% of patients; hypertension and palmar-plantar erythrodysesthesia syndrome were the most common adverse events (AEs), with rates for both reaching 29.4%, and a further phase III experiment (NCT05145218) is recruiting patients (Lan et al., 2022).

Cediranib is an oral small-molecule multitarget tyrosine kinase inhibitor that targets VEGFR-1, VEGFR-2, VEGFR-3 and c-kit that has shown antitumor activity against recurrent EOC (Matulonis et al., 2009). Matulonis et al. conducted a phase II study of cediranib monotherapy in patients with recurrent OC and obtained an overall remission rate of 17% and a mPFS of 5.2 months; major adverse effects included grade 3 hypertension (46%), fatigue (24%), diarrhea (13%), and grade 2 hypothyroidism (56%) but no intestinal perforation or fistulas (Ledermann et al., 2021). Compared with previous studies on bevacizumab monotherapy, the advantage is that when PFS is prolonged, the incidence of intestinal perforation or fistula treated with cediranib monotherapy is lower (Cannistra et al., 2007; Burger et al., 2007). It is worth noting that, on the one hand, cediranib targets vascular endothelial growth factor receptor (VEGFR) to induce HRD inhibition related to the hypoxic microenvironment, including the downregulation of HRR protein expression (Lu et al., 2011; Lim et al., 2014); on the other hand, cediranib inhibits platelet-derived growth factor receptor (PDGFR) and activates protein phosphatase 2A (PP2A), which mediates the inhibition of HRDs unrelated to hypoxia (Kaplan et al., 2019). Therefore, a series of clinical experiments were carried out on cediranib in combination with PARPis. ICON6 and ICON9 are phase III clinical trials for patients with PSROC. As of 2016, the mPFS in ICON6 in the chemotherapy plus cediranib and placebo maintenance therapy groups was 11.0 months and 8.7 months, respectively (p < 0.0001) (Ledermann et al., 2021). The ICON6 study demonstrated that cediranib maintenance therapy prolongs mPFS more effectively. However, ICON9 research focuses on the difference in the effectiveness of olaparib single-drug maintenance therapy or olaparib in combination with cediranib treatment. At present, patients are being recruited, and we look forward to the publishing of the results (Elyashiv et al., 2021). Interestingly, a preclinical study carried out by Francesca Bizzaro et al. found that for patients with OC xenotransplantation (OC-PDX), olaparib and cediranib played a synergistic role by affecting tumor cells and the TME, respectively. Regardless of the HRR mutation status, cediranib combined with olaparib shows a wider effect of inhibiting tumor vascular growth than the single drug in OC-PDX (Lheureux et al., 2020). A small study found that when the PARPi drug resistance mechanism is different, the antitumor activity of cediranib and olaparib will also change, just as their efficacy in patients with homologous recombination gene and/or ABCB1 reverse mutations is poor (Zimmer et al., 2019). Another phase I study (NCT02484404) of the combination of olaparib plus cediranib and durvalumab in patients with recurrent platinum-resistant OC found this combination to be tolerable and initially active; thus, the study has moved into a second phase of enrolling more patients with recurrent OC (Zimmer et al., 2019). We expect more practical strategies for the posterior-line treatment of patients with recurrent OC.

Poly (ADP-ribose) polymerase (PARP) is a key factor involved in DNA damage repair; on the one hand, PARP is involved in DNA single-strand break (SSB) repair-dependent base excision repair (BER) (Figure 3) (Banerjee et al., 2021); on the other hand, in double-strand break (DSB) repair, PARP contributes to HRR and inhibits error-prone non-homologous and microhomologous-mediated end-joining repair (Mirza et al., 2018). By competitively binding to NAD⁺, PARPis interfere with BER and inhibit PARP protein activity to prevent or slow down replication divergence, ultimately leading to SSB to DSB progression (Dziadkowiec et al., 2016). In addition, PARPis promote the capture of PARP proteins at the site of DNA damage, leading to a sustained S phase in cells, and the captured PARP-DNA complexes have been shown to be more cytotoxic than unrepaired SSBs (Murai et al., 2012; Gourley et al., 2019). Thus, PARPis enable error-prone repair processes to dominate and exert synthetic lethal effects in cells accompanied by mutations in HRR-associated genes. Many PARPis, such as olaparib, rucaparib, niraparib, pamiparib (BGB-290), and fuzuloparib, play an irreplaceable role in the first-line maintenance treatment and second-line and beyond posttreatment of OC.

Folate receptor α (FRα) is a cell surface transmembrane glycoprotein whose main role is to transport folate to promote cell proliferation and DNA synthesis, and its overexpression is closely associated with an increased metabolic demand for single carbon units in tumor cells. FRα is also involved in cancer cell division and migration, and the inhibition of this receptor provides a degree of direct anticancer activity (Scaranti et al., 2020). Because the percentage of EOC tumors with FRα overexpression is close to 80%, targeting FRα has become a promising treatment for EOC (O'Malley et al., 2020; Köbel et al., 2014).

Mirvetuximab soravtansine (IMGN853, MIRV), a first-in-class ADC consisting of a folate receptor alpha-binding antibody, a cleavable linker, and the maytansinoid payload DM4 (a potent microtubulin-targeting agent), causes cycle arrest and apoptosis in targeted cancer cells, and the drug has shown promising activity in women with platinum-based chemoresistant OC (Ponte et al., 2016). At the 2021 ASCO Annual Meeting, partial FORWARD II trial results were reported, and the investigators found strong antitumor activity and tolerability of MIRV in combination with bevacizumab in patients with FRα (+) OC with unknown platinum sensitivity. Based on previously reported data on MIRV/BEV in patients with platinum-resistant OC, this study suggests that MIRV + bevacizumab has the potential to be the combination of choice for patients with FRα-high expressing recurrent OC, regardless of platinum sensitivity (Lheureux et al., 2019a; Sisay and Edessa, 2017). The SORAYA trial enrolled a total of 106 patients with platinum-resistant OC with high FRα expression who had received up to three prior treatment regimens, at least one of which included bevacizumab. First-line data from SORAYA were presented at the 2022 SGO Annual Meeting, and an ORR of 32.4% and a median DOR of 6.9 months for the overall efficacy population were reported. Eighty-six percent of patients experienced all-grade AEs. Most AEs were of lower grade, with donor keratopathy and blurred vision, occurring in 47% of patients, being labeled as mirvetuximab sorafenib-specific AEs (SGO, 2022; Zamarin et al., 2020). In another phase III study, benefits of MIRV treatment compared to chemotherapy were demonstrated in terms of improvements in the secondary study endpoints of the ORR, CA-125 and patient-reported outcomes, and MIRV demonstrated a more manageable safety profile (Moore et al., 2021). In 2022, MIRV was approved by the FDA for application in the treatment of (FR α)-positive, platinum-resistant EOC (Figure 1).

Important processes of antitumor immunity include adaptive and natural immunity, which rely mainly on the recognition of tumor-associated antigens (TAAs) and tumor-specific antigens (TSAs) by immune cells (Figure 4) (Gajewski et al., 2013). OC tumors are immunogenic, and non-spontaneous antitumor immune responses can be detected in the tumors, peripheral blood and ascites of patients with EOCs (Morand et al., 2021). The histological marker of OC tumor immune recognition is tumor infiltrating lymphocytes (TILs) (Duraiswamy et al., 2021). The presence of CD3⁺ and CD8⁺ TILs in the OC TME has been demonstrated, and their recruitment is associated with a good prognosis in patients with EOC (Zhang et al., 2003; Santoiemma et al., 2016). Notably, the response rate of OC to ICIs remains suboptimal, with only 10%–15% of patients treated with single-agent ICIs showing good clinical outcomes (Chambers et al., 2021).

The main reason for this suboptimal response rate is that solid tumors, including OC, have a remodeling effect on the tumor immune microenvironment (TIM) (Figure 4) (Yang et al., 2022). On the one hand, tumor cells can alter the degree of infiltration as well as the phenotype and function of the TILs present in primary or metastatic tumor tissues directly or through the TME, leading to immune escape (Rådestad et al., 2018). On the other hand, by altering the expression of immune checkpoint-associated proteins, the activity of effector T-cell is suppressed, and the tumor-associated macrophage (TAM) phenotype is induced to convert from an inflammation-inducing M1 type to an anti-inflammatory M2 type. Thus, the efficacy of immunotherapy is closely related to the inflammatory status of the tumor site (An and Yang, 2020). Single-cell transcriptomic analysis of OC ascites and tumors confirmed significant differences in the composition and phenotype of immune cells and immunosuppressive cells in the liquid and solid TME (Zhang et al., 2018; Izar et al., 2020). According to Daniel S. Chen et al., the human TIM is grouped into three main phenotypes: inflammatory tumors, which are hot tumors in which many inflammatory cells and inflammatory factors represented by T-cell infiltrate the tumor parenchyma; immune death tumors, which are cold tumors in which there is a lack of T-cell infiltration in the tumor parenchyma or stroma; and immune rejection immune cells in the stroma, which surround the cancer nest with abundant characteristic immune cells but do not penetrate the tumor parenchyma (Hegde and Chen, 2020). For example, platinum-resistant OC that progresses within 6 months after platinum therapy exhibits a series of “cold tumor” features, namely, low infiltration of CD8 T-cell (Mariya et al., 2014) but increased activation of CD4 T-cell, increased infiltration of regulatory T-cell (Tregs) (Hao et al., 2018) and increased infiltration of PD-L1 cells (Hamanishi et al., 2015), known to promote peritoneal dissemination (Abiko et al., 2013), in which tumor cells are in an immunosuppressive microenvironment with enhanced proliferation and migration.

Based on the immunosuppressive microenvironment of OC and the background of poor responsiveness to ICIs alone, this review focuses on the combination of ICIs with other therapeutic approaches (Table 3). The combination of ICIs with different sites of action demonstrated some therapeutic efficacy.

In a study that included 100 patients with persistent or recurrent EOC, the efficacy and safety of nivolumab (a human lgG4 anti-PD-1 receptor blocking monoclonal antibody (mAb)) in combination with ipilimumab (a recombinant IgG1 human mAb against CTLA-4) were compared with those of nivolumab monotherapy. The results showed a longer PFS in the nivolumab + ipilimumab group than in the nivolumab group (3.9months vs 2 months). The rate of grade ≥3-related AEs was slightly higher in the nivolumab + ipilimumab group than in the nivolumab group (49%vs 33%). This result suggests that despite slightly higher toxicity, the combination regimen was associated with a higher response rate and longer mPFS than the single-agent regimen, suggesting that a large study should be conducted to better assess the efficacy and safety of the combination regimen (Zamarin et al., 2020). In another study (NCT02335918), it was observed in OC patients that varlilumab, a fully human agonist anti-CD27 mAb in combination with nivolumab, did not show toxicity beyond that of either monotherapy, and prolonged PFS was more pronounced at a ≥5% increase in tumor PD-L1 and intratumoral T-cell infiltration (Sanborn et al., 2022). High VEGF stimulates the expansion of immunosuppressive cells, including Tregs and myeloid-derived suppressor cells (MDSCs), inhibits the migration of immunoreactive T-cell to the TME and promotes their apoptosis, providing a theoretical basis for the combination of angiogenesis inhibitors and ICIs (Figure 4) (Fukumura et al., 2018). In a phase II (NCT02853318) non-randomized clinical trial, the combination of pembrolizumab with bevacizumab and oral cyclophosphamide was well tolerated, showing a clinical benefit and durable treatment response (>12 months) in 95.0% of patients with recurrent OC; this combination may represent a future treatment strategy for recurrent OC (Zsiros et al., 2021) In addition, niraparib further increases immune cell infiltration in the TIM and modulates immune activity by upregulating the activity of interferon genes and interferon pathway stimulators and PD-L1 expression on the tumor cell surface, which may make the combination of niraparib and ICI more toxic (Shen et al., 2019; Wang et al., 2019b). A single-arm phase I and II trial (NCT02657889) subgroup analysis showed that niraparib combined with pembrolizumab showed an ORR benefit regardless of platinum chemosensitivity status, prior bevacizumab treatment or tumor BRCA or HRD biomarker status (Konstantinopoulos et al., 2019). Interestingly, Appleton et al. constructed a three-dimensional spheroid culture model of OC patient origin and demonstrated that either pembrolizumab or durvalumab synergized with olaparib to reduce the viability of the in vitro model (Appleton et al., 2021). Platinum-based chemotherapy is known to induce T-cell proliferation and activation, suggesting that the combination of ICIs may have a synergistic effect (Fucikova et al., 2022). In a study including nine patients with recurrent platinum-resistant OC (NCT03029598), pembrolizumab combined with carboplatin was effective and well tolerated; 23 patients achieved optimal objective remission, with 10.3% in partial remission (PR) and 51.7% with stable disease (SD), in addition to 17.2% with PD (Liao et al., 2021). In OC with BRCA1/2 mutations, the tumor load is increased and TILs are increased; furthermore, PD1/PD-L1 expression is upregulated in response to multiple interferon γ, P53 and BRCA mutations, thus possibly leading to greater sensitivity to PD1/PD-1 inhibitors (Jiang et al., 2021). In patients with PROC, the study by Li et al. suggested that the ORR and mPFS of PLD combined with pembrolizumab treatment were higher than those of the respective monotherapy, but with the inclusion of 23 patients in this study, a larger study is needed for validation (Lee et al., 2020).

EOC responds poorly to ICIs due to its immunological features, including limited tumor mutational load (TMB) and poor lymphocyte infiltration. The use of immune vaccines and lysoviral therapy is a new strategy to enhance antitumor immunity in OC. A completed phase II clinical study, SOV01 (NCT02107937), found a statistically significant improvement in PFS with the addition of autologous dendritic cell immunotherapy (DCVAC) to first-line standard chemotherapy with carboplatin and paclitaxel (Rob et al., 2022). Interestingly, the clinical benefit of DCVAC was more pronounced in OC patients than in prostate and lung cancer patients, despite an antitumor immune cycle characterized by reduced expression of T-cell-associated genes (Hensler et al., 2022). However, multiple mechanisms, including the restriction of dendritic cell (DC) migration to draining lymph nodes, the immunosuppressive tumor microenvironment (TME) in OC, and metabolic restriction of tumor-associated DC activation, may lead to limited clinical efficacy of DC vaccines (O'Neill and Pearce, 2016). In this regard, several in vitro and preclinical studies have provided evidence that modified DC vaccines have shown greater benefit in OC treatment (Cheng et al., 2020).

In 2018, TANYI et al. used a personalized vaccine generated by autologous DCs pulsed with oxidized autologous whole-tumor cells. After the administration of a personalized vaccine generated by autologous DCs pulsed with oxidized autologous whole-tumor cell lysate (OCDC), an increase in IFN-γ-producing T-cell responsive to DC-presented tumor antigens was detected, with a significantly higher 2-year OS in patients who responded to the vaccine than in those who did not (100% vs 25%) and with good tolerability (Tanyi et al., 2018). In addition, Wen Zhang et al. found that the immune responses triggered by DC vaccines prepared with Wilms’ tumor protein 1 (WT1) peptides in patients with advanced OC were significantly associated with a decrease in bone marrow-derived suppressor cells (p = 0.045) in pretreated peripheral blood, which suggests the potential therapeutic effect of such vaccines (Zhang et al., 2019a). Recently, based on NY-ESO-1 fused with SecPen and ubiquitin, Yunkai Yang and his colleagues prepared a novel DC vaccine (DC-SNU) that induced stronger and specific T-cell immunity in mice (Yang et al., 2021b). In addition, in patients with advanced OC, long-term toxicity was not observed before or after the injection of a Th1 selective IGFBP-2 N-terminus vaccine, and T-cell clones were significantly upregulated (p = 0.03) (Cecil et al., 2021).

Selective infection and direct lysis of tumor cells by an oncolytic virus (OV) leads to the release of viral particles, cytokines and other tumor cell contents, and the release of various substances triggers innate and adaptive proinflammatory immune responses against tumor cells (Cook and Chauhan, 2020). For example, the treatment of cells from patients with OC with an oncolytic adenovirus (Ad5/3-E2F-D24-hTNFa-IRES-hIL2) in isolated cultures reshaped the OC immune microenvironment, activating CD4⁺ and CD8⁺ TILs, which in turn enhanced antitumor responsiveness (Santos et al., 2020). OVs have shown efficacy in preclinical models of advanced EOC, and it is significant that the interaction of PD-1 with its ligands PD-L1 and PD-L2 leads to the suppression of T and NK cells without overlapping with OV-mediated activation pathways (van Vloten et al., 2022). In the advanced EOCID8 model, Parapoxvirus ovis (Orf virus (OrfV)) treatment promoted active recruitment of NK cells in tumor cells and in the ascites TME, stimulated a strong antitumor response, activated NK cells and further induced T-cell recruitment in the OC TME through the CXCR3 chemokine axis, prolonging mouse survival (van Vloten et al., 2022). In a recent study, Lei et al. innovatively used the human IgG family as a scaffold to construct anti-CD47 mAbs piggybacking on tumor soluble herpesvirus (oHSV). This oncolytic herpes simplex virus, which maximizes Fc receptor-mediated antitumor effects and expresses anti-CD47 antibodies to block “do not eat me” signaling, has therapeutic effects (Tian et al., 2022).

Oncolytic herpes simplex virus (HSV) treatment of mice with OC carrying a platinum resistance gene disrupts the extracellular vesicle (EV) pathway associated with cisplatin efflux, not only helping to prevent drug resistance but also promoting DNA damage to activate the immune system and innate immunity and enhance the efficacy against ICIs (Hong et al., 2021). Novel active virus-like nanoparticle (VLP) delivery vehicles are more widely distributed and more long-lasting in OC ground metastatic ascites and have been shown to help improve survival in mice with peritoneal metastases from OC (Wang et al., 2020). In Table 4, we summarize all recent clinical trials using oncolytic viruses in the treatment of OC.