Review Article: Intratumoral Immunotherapy: Old Discoveries and Recent Developments in Sarcomas

Intratumoral immunotherapy represents a promising frontier in the treatment of sarcomas, aiming to transform immunologically "cold" tumors into "hot" ones capable of generating systemic antitumor responses. Building on William Coley's early work with bacterial infections, modern intratumoral therapies induce the cancer immunity cycle by delivering immune-activating agents directly into tumors to stimulate local and systemic immunity while minimizing systemic toxicity. This review summarizes key strategies under investigation for sarcomas, including cancer vaccines (e.g., LTX-315), cytokines and immunomodulators (e.g., STING agonists), pattern recognition receptor agonists (e.g., TLR4/9 agonists), oncolytic virotherapy (e.g., T-VEC, JX-594), cytotoxic agents (e.g., INT230-6), and cell-based therapies (e.g., dendritic cell injections). These agents are also being evaluated in combination with systemic immunotherapies and local therapies such as radiation. Early clinical trials and preclinical studies demonstrate feasibility, safety, and signs of immune activation, though consistent clinical efficacy remains to be established. Since sarcomas typically exhibit poor immunogenicity due to low tumor mutational burden and immunosuppressive tumor microenvironments, future research is needed to optimize delivery strategies, identify predictive biomarkers, and integrate intratumoral approaches with other emerging immunotherapies to induce the cancer immunity cycle. Collectively, intratumoral immunotherapy may play a transformative role in overcoming resistance and enhancing outcomes for patients with sarcoma.