{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T08:53:24Z","timestamp":1791363204050,"version":"4.3.1"},"reference-count":38,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006108","name":"NIH National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","award":["UL1TR002373"],"award-info":[{"award-number":["UL1TR002373"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]},{"award":["UL1TR002373"],"award-info":[{"award-number":["UL1TR002373"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Merkel cell carcinoma (MCC) represents a rare but highly aggressive neuroendocrine skin cancer with limited systemic therapy options for patients who fail or are ineligible for immune checkpoint inhibitors (ICIs). Intratumoral (IT) immunotherapy has emerged as a promising strategy, leveraging the accessibility of tumor lesions and their inherent capacity to trigger immune responses, known as abscopal effects. This review synthesizes the current evidence on IT approaches in MCC, including Toll-like receptor agonists, cytokines, and oncolytic viruses, and highlights their distinct mechanisms of action, while emphasizing the critical need for standardized radiographic response assessment of injected and non-injected lesions. Inconsistent documentation of abscopal responses has hindered quantification of IT therapy\u2019s systemic potential, particularly in a disease where one-third of patients present with metastases and distant relapse is common. We outline MCC-specific rationale for routine lesion-level tracking, and recommendations for IT trial designs and objectives. Rigorous assessments of abscopal data will clarify IT\u2019s role as both rescue therapy and an ICI partner, potentially transforming outcomes in this refractory MCC.<\/jats:p>","DOI":"10.3390\/cancers18193226","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T08:28:57Z","timestamp":1791361737000},"page":"3226","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Intratumoral Immunotherapy\u2014The Future of Treating Merkel Cell Carcinoma?"],"prefix":"10.3390","volume":"18","author":[{"given":"Nayonika","family":"Pande","sequence":"first","affiliation":[{"name":"University of Texas at Austin, Austin, TX 78712, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin C.","family":"Moser","sequence":"additional","affiliation":[{"name":"HonorHealth Research Institute, Scottsdale, AZ 85258, USA"},{"name":"Arizona State John Shufeldt School of Medicine and Medical Engineering, Phoenix, AZ 85004, USA"},{"name":"Department of Internal Medicine, University of Arizona College of Medicine, Phoenix, AZ 85004, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjay","family":"Chandrasekaran","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Texas Southwestern, Dallas, TX 75390, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0071-0534","authenticated-orcid":false,"given":"Andrew S.","family":"Brohl","sequence":"additional","affiliation":[{"name":"Moffitt Cancer Center, Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2191-4085","authenticated-orcid":false,"given":"Rajan P.","family":"Kulkarni","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Oregon Health and Sciences University, Portland, OR 97239, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8417-2787","authenticated-orcid":false,"given":"Vincent T.","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Hematology, Medical Oncology, and Palliative Care, University of Wisconsin-Madison, Madison, WI 53792, USA"},{"name":"Department of Dermatology, University of Wisconsin-Madison, Madison, WI 53792, USA"},{"name":"University of Wisconsin Carbone Cancer Center, 600 Highland Ave, K4\/550, Madison, WI 53792, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,10,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1016\/j.jaad.2025.05.001","article-title":"The epidemiology of Merkel cell carcinoma in the United States","volume":"93","author":"Fakult","year":"2025","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1007\/s00262-017-2099-3","article-title":"Epidemiology, biology and therapy of Merkel cell carcinoma: Conclusions from the EU project IMMOMEC\u2014Nghiem Lab","volume":"67","author":"Becker","year":"2018","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1158\/1078-0432.CCR-18-0469","article-title":"Intratumoral G100, a TLR4 Agonist, Induces Antitumor Immune Responses and Tumor Regression in Patients with Merkel Cell Carcinoma","volume":"25","author":"Bhatia","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1631","DOI":"10.1158\/2159-8290.CD-23-0798","article-title":"Preexisting Skin-Resident CD8 and \u03b3\u03b4 T-Cell Circuits Mediate Immune Response in Merkel Cell Carcinoma and Predict Immunotherapy Efficacy","volume":"14","author":"Reinstein","year":"2024","journal-title":"Cancer Discov."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s40425-018-0335-9","article-title":"Immunotherapy for Merkel cell carcinoma: A turning point in patient care","volume":"6","author":"Chan","year":"2018","journal-title":"J. Immunother. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e000674","DOI":"10.1136\/jitc-2020-000674","article-title":"Avelumab in patients with previously treated metastatic Merkel cell carcinoma: Long-term data and biomarker analyses from the single-arm phase 2 JAVELIN Merkel 200 trial","volume":"8","author":"Bhatia","year":"2020","journal-title":"J. Immunother. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2542","DOI":"10.1056\/NEJMoa1603702","article-title":"PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma","volume":"374","author":"Nghiem","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e012478","DOI":"10.1136\/jitc-2025-012478","article-title":"Phase II study of retifanlimab in patients with recurrent locally advanced or metastatic Merkel cell carcinoma (POD1UM-201)","volume":"13","author":"Grignani","year":"2025","journal-title":"J. Immunother. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1007\/s00262-026-04313-2","article-title":"First-line ipilimumab plus nivolumab in advanced merkel cell carcinoma: A meta-analysis of prospective trials and real-world validation cohort","volume":"75","author":"Ramadoss","year":"2026","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Migden, M.R., Chai-Ho, W., Daniels, G.A., Medina, T., Wise-Draper, T.M., Kheterpal, M., Tang, J.C., Ibrahim, S.F., Bolotin, D., and Verschraegen, C. (2024, January 5\u201310). Initial Results from an Open-Label Phase 1b\/2 Study of RP1 Oncolytic Immunotherapy in Solid Organ Transplant Recipients with Advanced Cutaneous Malignancies (ARTACUS). Proceedings of the 115th Annual Meeting of the American Association for Cancer Research, San Diego, CA, USA.","DOI":"10.1158\/1538-7445.AM2024-CT003"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2667","DOI":"10.1200\/JCO.19.02985","article-title":"Response Criteria for Intratumoral Immunotherapy in Solid Tumors: itRECIST","volume":"38","author":"Goldmacher","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"10039","DOI":"10.2147\/OTT.S247050","article-title":"Toll-Like Receptor 9 Agonists in Cancer","volume":"13","author":"Karapetyan","year":"2020","journal-title":"OncoTargets Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e011651","DOI":"10.1136\/jitc-2025-011651","article-title":"Phase 1b\/2 study evaluating safety, efficacy and immune effects of TLR9 agonist cavrotolimod with anti-PD-1 antibodies among patients with advanced solid tumors","volume":"13","author":"Milhem","year":"2025","journal-title":"J. Immunother. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1158\/1078-0432.CCR-19-0972","article-title":"Intratumoral Delivery of Plasmid IL12 Via Electroporation Leads to Regression of Injected and Noninjected Tumors in Merkel Cell Carcinoma","volume":"26","author":"Bhatia","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"705","DOI":"10.2217\/imt-2019-0033","article-title":"Talimogene Laherparepvec: Review of its Mechanism of Action and Clinical Efficacy and Safety","volume":"11","author":"Raman","year":"2019","journal-title":"Immunotherapy"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1016\/j.jdcr.2019.06.034","article-title":"Talimogene laherparepvec induces durable response of regionally advanced Merkel cell carcinoma in 4 consecutive patients","volume":"5","author":"Westbrook","year":"2019","journal-title":"JAAD Case Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4985","DOI":"10.1245\/s10434-026-19182-3","article-title":"Evaluation of Talimogene Laherparepvec for the Treatment of Advanced Nonmelanoma Skin Cancers","volume":"33","author":"Slatton","year":"2026","journal-title":"Ann. Surg. Oncol."},{"key":"ref_18","first-page":"A715","article-title":"Interim analysis of a phase II study of talimogene laherparepvec (T-VEC) followed by combination T-VEC + nivolumab in non-melanoma skin cancers and refractory cutaneous lymphoma (NCI#10057)","volume":"12","author":"Silk","year":"2024","journal-title":"J. Immunother. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"110478","DOI":"10.1016\/j.radonc.2024.110478","article-title":"A phase II randomized trial of talimogene laherparepvec oncolytic immunotherapy with or without radiotherapy for patients with cutaneous metastases from solid tumors","volume":"200","author":"Barker","year":"2024","journal-title":"Radiother. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e013692","DOI":"10.1136\/jitc-2025-013692","article-title":"Effects of oncolytic immunotherapy with RP1 (vusolimogene oderparepvec) on immune cells mediate responsiveness to anti-PD-1 via STING-mediated interferon signaling","volume":"14","author":"Roulstone","year":"2026","journal-title":"J. Immunother. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Schadendorf, D., Wong, M.K., Beasley, G.M., Wise-Draper, T.M., Michels, J., Arance, A., Amini-Adle, M., Zhu, J., Viana, M., and Hou, J.W. (2026, January 23\u201325). Efficacy and Safety of RP1 Plus Nivolumab in Patients with Non-Melanoma Skin Cancer. Proceedings of the 22nd European Association of Dermato-Oncology (EADO) Congress, Prague, Czech Republic.","DOI":"10.1016\/j.ejcskn.2026.100982"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"9592","DOI":"10.1200\/JCO.2024.42.16_suppl.9592","article-title":"Phase 1b trial of IFx-Hu2.0, a novel in situ cancer vaccine, in checkpoint inhibitor-resistant Merkel cell carcinoma (MCC) and cutaneous squamous cell carcinoma (cSCC)","volume":"42","author":"Brohl","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1158\/1078-0432.CCR-21-1963","article-title":"Phase I Dose-Escalation Trial of MIW815 (ADU-S100), an Intratumoral STING Agonist, in Patients with Advanced\/Metastatic Solid Tumors or Lymphomas","volume":"28","author":"Sweis","year":"2022","journal-title":"Clin. Cancer Res."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Cuiffo, B., Maxwell, M., Yan, D., Guemiri, R., Boone, A., Bellet, D., Rivest, B., Cardia, J., Robert, C., and Fricker, S.P. (2024). Self-delivering RNAi immunotherapeutic PH-762 silences PD-1 to generate local and abscopal antitumor efficacy. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1501679"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"TPS9612","DOI":"10.1200\/JCO.2025.43.16_suppl.TPS9612","article-title":"Trial in progress: A phase 3 randomized study of low-dose intralesional cemiplimab versus primary surgery for patients with early-stage cutaneous squamous cell carcinoma (CLEAR CSCC)","volume":"43","author":"Migden","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"xii33","DOI":"10.1093\/annonc\/mdx683","article-title":"Intratumoral immunotherapy: Using the tumor as the remedy","volume":"28","author":"Marabelle","year":"2017","journal-title":"Ann. Oncol."},{"key":"ref_27","unstructured":"(2026, April 27). Investigating the Abscopal Effect as a Treatment for Cancer, Available online: https:\/\/www.cancer.gov\/news-events\/cancer-currents-blog\/2020\/cancer-abscopal-effect-radiation-immunotherapy."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.ctrv.2005.03.004","article-title":"The controversial abscopal effect","volume":"31","author":"Kaminski","year":"2005","journal-title":"Cancer Treat. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.1002\/cam4.2781","article-title":"Patterns of distant metastases in 215 Merkel cell carcinoma patients: Implications for prognosis and surveillance","volume":"9","author":"Lewis","year":"2020","journal-title":"Cancer Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3151","DOI":"10.1200\/JCO.23.02054","article-title":"Circulating Tumor DNA Assay Detects Merkel Cell Carcinoma Recurrence, Disease Progression, and Minimal Residual Disease: Surveillance and Prognostic Implications","volume":"42","author":"Akaike","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1464","DOI":"10.1002\/cncr.30475","article-title":"Viral oncoprotein antibodies as a marker for recurrence of Merkel cell carcinoma: A prospective validation study","volume":"123","author":"Paulson","year":"2017","journal-title":"Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Li, H., Lv, S., Meng, W., Guo, J., Lu, Y., Peng, L., Chen, W., Yang, W., and Peng, X. (2026). Radiotherapy and tertiary lymphoid structures: Balancing immune activation and immune damage in cancer immunotherapy. Mol. Cancer.","DOI":"10.1186\/s12943-026-02735-1"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4169","DOI":"10.1245\/s10434-016-5286-0","article-title":"Patterns of Clinical Response with Talimogene Laherparepvec (T-VEC) in Patients with Melanoma Treated in the OPTiM Phase III Clinical Trial","volume":"23","author":"Andtbacka","year":"2016","journal-title":"Ann. Surg. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.1038\/s41591-021-01510-7","article-title":"Neoadjuvant talimogene laherparepvec plus surgery versus surgery alone for resectable stage IIIB-IVM1a melanoma: A randomized, open-label, phase 2 trial","volume":"27","author":"Dummer","year":"2021","journal-title":"Nat. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1016\/j.jaad.2024.05.095","article-title":"Current and emerging intralesional immunotherapies in cutaneous oncology","volume":"91","author":"Stull","year":"2024","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1093\/annonc\/mdz187","article-title":"Pre-treated anti-PD-1 refractory Merkel cell carcinoma successfully treated with the combination of PD-1\/PD-L1 axis inhibitors and TVEC: A report of two cases","volume":"30","author":"Knackstedt","year":"2019","journal-title":"Ann. Oncol."},{"key":"ref_37","unstructured":"U.S. Food and Drug Administration (2026, September 26). Cellular, Tissue, and Gene Therapies Advisory Committee Meeting Briefing Document: RP1 (vusolimogene oderparepvec) with Nivolumab for Advanced Melanoma, Available online: https:\/\/www.fda.gov\/media\/193878\/download."},{"key":"ref_38","unstructured":"Replimune Group, Inc. (2026, September 26). Replimune Receives Complete Response Letter from the FDA for RP1 Biologics License Application for the Treatment of Advanced Melanoma. Available online: https:\/\/ir.replimune.com\/news-releases\/news-release-details\/replimune-receives-complete-response-letter-fda-rp1-biologics-0."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/19\/3226\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T08:36:13Z","timestamp":1791362173000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/19\/3226"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,7]]},"references-count":38,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["cancers18193226"],"URL":"https:\/\/doi.org\/10.3390\/cancers18193226","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,7]]}}}